HIV inhibiting bicyclic pyrimidine derivatives

ABSTRACT

HIV replication inhibitors of formula 
                         
N-oxides, pharmaceutically acceptable addition salts, quaternary amines or stereoisomeric forms thereof, wherein
     -a 1 =a 2 -a 3 =a 4 - is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; -b 1 =b 2 -b 3 =b 4 - is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—;   n and m is 0, 1, 2, 3 and in certain cases also 4;   R 1  is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; optionally substituted C 1-6 alkyl; C 1-6 alkyloxycarbonyl;   R 2  is OH; halo; optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; substituted carbonyl; carboxyl; CN; nitro; amino; substituted amino; polyhalomethyl; polyhalomethylthio; —S(═O) p R 6 ; C(═NH)R 6 ;   R 2a  is CN; amino; substituted amino; optionally substituted C 1-6 alkyl; halo; optionally substituted C 1-6 alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R 16 ; optionally substituted C 1-6 alkyloxyC 1-6 alkyl; substituted C 2-6 alkenyl or C 2-6 alkynyl; —C(═N—O—R 8 )—C 1-4 alkyl; R 7  or —X—R 7 ;   R 3  is CN; amino; C 1-6 alkyl; halo; optionally substituted C 1-6 alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R 16 ; substituted C 1-6 alkyl; optionally substituted C 1-6 alkyloxyC 1-6 alkyl; substituted C 2-6 alkenyl or C 2-6 alkynyl; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; —X—R 7 ;   R 4  is halo; OH; optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; C 3-7 cycloalkyl; C 1-6 alkyloxy; CN; nitro; polyhaloC 1-6 alkyl; polyhaloC 1-6 alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C 1-4 alkyl)amino or R 7 ;   -A-B— is —CR 5 ═N—, —N═N—, —CH 2 —CH 2 —, —CS—NH—, —CO—NH—, —CH═CH—;
 
pharmaceutical compositions comprising these; methods for the preparation of these compounds and compositions; the use of these compounds for the prevention or the treatment of HIV infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/410,779, filed on Mar. 2, 2012, which is a divisional of U.S.application Ser. No. 11/718,181, filed on Apr. 27, 2007, now U.S. Pat.No. 8,153,640, which in turn is a national stage application of PCTPatent Application No. PCT/EP2005/055589, filed on Oct. 27, 2005, whichapplication claims priority from EPO Patent Application No. 04105419.8,filed on Oct. 29, 2004, all of which are hereby incorporated byreference in their entirety.

The present invention is concerned with pyrimidine derivatives havingHIV (Human Immunodeficiency Virus) replication inhibiting properties.The invention further relates to methods for their preparation andpharmaceutical compositions comprising them. The invention also relatesto the use of said compounds in the prevention or the treatment of HIVinfection.

Resistance of the HIV virus against currently available HIV drugscontinues to be a major cause of therapy failure. This has led to theintroduction of combination therapy of two or more anti-HIV agentsusually having a different activity profile. Significant progress wasmade by the introduction of HAART therapy (Highly Active Anti-RetroviralTherapy), which has resulted in a significant reduction of morbidity andmortality in HIV patient populations treated therewith. HAART involvesvarious combinations of nucleoside reverse transcriptase inhibitors(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) andprotease inhibitors (PIs). Current guidelines for antiretroviral therapyrecommend such triple combination therapy regimen for initial treatment.However, these multidrug therapies do not completely eliminate HIV andlong-term treatment usually results in multidrug resistance. Inparticular, half of the patients receiving anti-HIV combination therapydo not respond fully to the treatment, mainly because of resistance ofthe virus to one or more drugs used. It also has been shown thatresistant virus is carried over to newly infected individuals, resultingin severely limited therapy options for these drug-naive patients.

Therefore there is a continued need for new combinations of activeingredients that are effective against HIV. New types of anti-HIVeffective active ingredients, differing in chemical structure andactivity profile are useful in new types of combination therapy Findingsuch active ingredients therefore is a highly desirable goal to achieve.

The present invention is aimed at providing particular novel series ofbicyclic derivatives having HIV replication inhibiting properties.WO-99/50250 , WO-00/27825 and WO-01/85700 disclose certain substitutedaminopyrimidines and WO-99/50256 and EP-A-834 507 discloseaminotriazines having HIV replication inhibiting properties. DD-21593describes a number of bisarylamino substituted purines as compoundshaving anti-fungal activity.

It now has been found that certain bisaryl substituted bicycles not onlyact favorably in terms of their capability to inhibit the replication ofHIV, but also by their improved ability to inhibit the replication ofmutant strains, in particular in strains which have become resistant toone or more known NNRTI drugs (Non Nucleoside Reverse TranscriptaseInhibitor drugs), which strains are referred to as drug or multidrugresistant HIV strains.

The present invention concerns compounds of formula

the N-oxides; the pharmaceutically acceptable addition salts; thequaternary amines; or the stereochemically isomeric forms thereof,wherein

-   -a¹=a²-a³=a⁴- represents a bivalent radical of formula    —CH═CH—CH═CH—  (a-1);    —N═CH—CH═CH—  (a-2);    —N═CH—N═CH—  (a-3);    —N═CH—CH═N—  (a-4);    —N═N—CH═CH—  (a-5);-   -b¹=b²-b³=b⁴- represents a bivalent radical of formula    —CH═CH—CH═CH—  (b-1);    —N═CH—CH═CH—  (b-2);    —N═CH—N═CH—  (b-3);    —N═CH—CH═N—  (b-4);    —N═N—CH═CH—  (b-5);-   n is 0, 1, 2, 3 and in case -a¹=a²-a³=a⁴- is (a-1), then n may also    be 4;-   m is 0, 1, 2, 3 and in case -b¹=b²-b³=b⁴- is (b-1), then m may also    be 4;-   -A-B— represents a bivalent radical of formula    —CR⁵═N—  (c-1);    —N═N—  (c-2);    —CH₂—CH₂—  (c-3);    —CS—NH—  (c-4);    —CO—NH—  (c-5);    —CH═CH—  (c-6);-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, or with C₁₋₆alkyloxycarbonyl;-   each R² independently is hydroxy; halo; C₁₋₆alkyl optionally    substituted with one, two or three substituents each independently    selected from halo, cyano and —C(═O)R⁶; C₃₋₇cycloalkyl; C₂₋₆alkenyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano and —C(═O)R⁶; C₂₋₆alkynyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano and —C(═O)R⁶;    C₁₋₆alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or    di(C₁₋₆alkyl)amino; polyhalomethyl; polyhalomethylthio;    —S(═O)_(p)R⁶; —NH—S(═O)_(p)R⁶; —C(═O)R⁶; —NHC(═O)H; —C(═O)NHNH₂;    NHC(═O)R⁶; C(═NH)R⁶;-   R^(2a) is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one, two or three    substituents each independently selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyloxyC₁₋₆alkyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkenyl substituted with one, two or    three substituents each independently selected from halo, cyano,    NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl    substituted with one, two or three substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X—R⁷;-   R³ is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one, two or three    substituents each independently selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyloxyC₁₋₆alkyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkenyl substituted with one, two or    three substituents each independently selected from halo, cyano,    NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl    substituted with one, two or three substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ and —X—R⁷;-   X is —NR¹—, —O—, —C(═O)—, —S—, —S(═O)_(p)—;-   each R⁴ independently is halo; hydroxy; C₁₋₆alkyl optionally    substituted with one, two or three substituents each independently    selected from halo, cyano and —C(═O)R⁶; C₂₋₆alkenyl optionally    substituted with one, two or three substituents each independently    selected from halo, cyano and —C(═O)R⁶; C₂₋₆alkynyl optionally    substituted with one, two or three substituents each independently    selected from halo, cyano and —C(═O)R⁶; C₃₋₇cycloalkyl;    C₁₋₆alkyloxy; cyano; nitro; polyhalo-C₁₋₆alkyl;    polyhaloC₁₋₆alkyloxy; aminocarbonyl; mono- or    di(C₁₋₄alkyl)amino-carbonyl; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylcarbonyl; formyl; amino; mono- or di(C₁₋₄alkyl)amino or R⁷;-   Q is hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, or —NR⁹R¹⁰;-   R⁵ is hydrogen, C₁₋₆alkyl, aryl, pyridyl, thienyl, furanyl, amino,    mono- or di(C₁₋₄alkyl)amino;-   R⁶ is C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino or    polyhaloC₁₋₄alkyl;-   R⁷ is a monocyclic, bicyclic or tricyclic saturated, partially    saturated or aromatic carbocycle or a monocyclic, bicyclic or    tricyclic saturated, partially saturated or aromatic heterocycle,    wherein each of said carbocyclic or heterocyclic ring systems may    optionally be substituted with one, two, three, four or five    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxy C₁₋₆alkyl, aminoC₁₋₆alkyl, mono and    di(C₁₋₆alkyl)amino C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio,    cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    aminocarbonyl, —CH(═N—O—R⁸), R^(7a), —X—R^(7a) and R^(7a)—C₁₋₄alkyl;-   R^(7a) is a monocyclic, bicyclic or tricyclic saturated, partially    saturated or aromatic carbocycle or a monocyclic, bicyclic or    tricyclic saturated, partially saturated or aromatic heterocycle,    wherein each of said carbocyclic or heterocyclic ring systems may    optionally be substituted with one, two, three, four or five    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)amino C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio,    cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl    and —CH(═N—O—R⁸);-   R⁸ is hydrogen, C₁₋₄alkyl, aryl or arylC₁₋₄alkyl;-   R⁹ and R¹⁰ each independently are hydrogen; hydroxy; C₁₋₆alkyl;    C₁₋₆alkyloxy; C₁₋₆alkyl-carbonyl; C₁₋₆alkyloxycarbonyl; amino; mono-    or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;    —CH(═NR¹¹) or R⁷, wherein each of the aforementioned C₁₋₆alkyl    groups may optionally and each individually be substituted with one    or two substituents each independently selected from hydroxy,    C₁₋₆alkyloxy, hydroxy-C₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,    cyano, amino, imino, mono- and) amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,    —C(═NH)R⁶, R⁷; or-   R⁹ and R¹⁰ may be taken together to form a bivalent or trivalent    radical of formula    —CH₂—CH₂—CH₂—CH₂—  (d-1)    —CH₂—CH₂—CH₂—CH₂—CH₂—  (d-2)    —CH₂—CH₂—O—CH₂—CH₂—  (d-3)    —CH₂—CH₂—S—CH₂—CH₂—  (d-4)    —CH₂—CH₂—NR¹²—CH₂—CH₂—  (d-5)    —CH₂—CH═CH—CH₂—  (d-6)    ═CH—CH═CH—CH═CH—  (d-7)-   R₁₁ is cyano; C₁₋₄alkyl optionally substituted with C₁₋₄alkyloxy,    cyano, amino, mono- or di(C₁₋₄alkyl)amino or aminocarbonyl;    C₁₋₄alkylcarbonyl; C₁₋₄alkyloxycarbonyl; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl;-   R¹² is hydrogen or C₁₋₄alkyl;-   R¹³ and R¹⁴ each independently are C₁₋₆alkyl optionally substituted    with cyano or aminocarbonyl, C₂₋₆alkenyl optionally substituted with    cyano or aminocarbonyl, C₂₋₆alkynyl optionally substituted with    cyano or aminocarbonyl;-   R¹⁵ is C₁₋₆alkyl substituted with cyano or aminocarbonyl;-   R¹⁶ is C₁₋₆alkyl optionally substituted with cyano or aminocarbonyl,    or R⁷;-   each p is 1 or 2;-   each aryl is phenyl or phenyl substituted with one, two, three, four    or five substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,    polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, a radical    Het and —X-Het;-   Het is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl,    pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl quinolinyl,    benzothienyl, benzofuranyl; which each may optionally be substituted    with one or two C₁₋₄alkyl radicals.

The present invention also relates to the use of a compound for themanufacture of a medicament for the treatment or prevention of HIVinfection, wherein the compound belongs to the group of compounds havingthe formula (I) or any of the subgroups of compounds as specifiedherein.

As used hereinbefore or hereinafter C₁₋₄alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as methyl, ethyl, propyl,1-methylethyl, butyl; C₁₋₆alkyl as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as the group defined for C₁₋₄alkyl and pentyl,hexyl, 2-methylbutyl and the like; C₁₋₂alkyl defines methyl and ethyl;C₂₋₆alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 2 to 6 carbon atomssuch as ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl,2-methylbutyl and the like; C₃₋₇cycloalkyl is generic to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C₂₋₆alkenyl definesstraight and branched chain hydrocarbon radicals having from 2 to 6carbon atoms containing a double bond such as ethenyl, propenyl,butenyl, pentenyl, hexenyl and the like; C₂₋₆alkynyl defines straightand branched chain hydrocarbon radicals having from 2 to 6 carbon atomscontaining a triple bond such as ethynyl, propynyl, butynyl, pentynyl,hexynyl and the like. Preferred amongst C₂₋₆alkenyl and C₂₋₆alkynyl arethe unsaturated analogs having from 2 to 4 carbon atoms, i.e.C₂₋₄alkenyl and C₂₋₄alkynyl respectively. Any C₂₋₆alkenyl or C₂₋₆alkynyllinked to a heteroatom preferably is connected to said heteroatom by asaturated carbon atom.

In a number of instances the radicals C₁₋₆alkynyl, C₂₋₆alkenyl, orC₂₋₆alkynyl may be substituted with one, two or three substituents.Preferably, said radicals are substituted with up to 2 substituents,more preferably with one substituent.

A monocyclic, bicyclic or tricyclic saturated carbocycle represents aring system consisting of 1, 2 or 3 rings, said ring system beingcomposed of only carbon atoms and said ring system containing onlysingle bonds; a monocyclic, bicyclic or tricyclic partially saturatedcarbocycle represents a ring system consisting of 1, 2 or 3 rings, saidring system being composed of only carbon atoms and comprising at leastone double bond provided that the ring system is not an aromatic ringsystem; a monocyclic, bicyclic or tricyclic aromatic carbocyclerepresents an aromatic ring system consisting of 1, 2 or 3 rings, saidring system being composed of only carbon atoms; the term aromatic iswell known to a person skilled in the art and designates cyclicallyconjugated systems of 4n+2 electrons, that is with 6, 10, 14 etc.π-electrons (rule of Hückel); a monocyclic, bicyclic or tricyclicsaturated heterocycle represents a ring system consisting of 1, 2 or 3rings and comprising at least one heteroatom selected from O, N or S,said ring system containing only single bonds; a monocyclic, bicyclic ortricyclic partially saturated heterocycle represents a ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S, and at least one double bond provided that thering system is not an aromatic ring system; a monocyclic, bicyclic ortricyclic aromatic heterocycle represents an aromatic ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S.

Particular examples of monocyclic, bicyclic or tricyclic saturatedcarbocycles are cyclo propyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[4,2,0]-octanyl, cyclononanyl,cyclodecanyl, decahydronapthalenyl, tetradecahydroanthracenyl and thelike. Preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl; more preferred are cyclopentyl, cyclohexyl, cycloheptyl.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[4,2,0]octenyl,cyclononenyl, cyclodecenyl, octahydronaphthalenyl,1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4,4a,9,9a,10-octahydro-anthracenyland the like.

Particular examples of monocyclic, bicyclic or tricyclic aromaticcarbocycles are phenyl, naphthalenyl, anthracenyl. Preferred is phenyl.

Particular examples of monocyclic, bicyclic or tricyclic saturatedheterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, tetrahydro-thienyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl,hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, trithianyl, decahydro-quinolinyl, octahydroindolyl and thelike. Preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, dihydrooxazolyl, triazolidinyl,piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl.Particularly preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, indolinyl and the like. Preferred arepyrrolinyl, imidazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,indolinyl.

Particular examples of monocyclic, bicyclic or tricyclic aromaticheterocycles are azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl,benzo-thienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl,benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzo-thiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolo-pyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolo-pyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolo-pyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, isoxazolo-triazinyl, isothiazolotriazinyl,pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl,imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl,triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

Preferred aromatic heterocycles are monocyclic or bicyclic aromaticheterocycles. Interesting monocyclic, bicyclic or tricyclic aromaticheterocycles are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl,isobenzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl,isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl,pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl,thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl,imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl,isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl,oxazolo-pyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl,pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl,isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl,oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl,oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl,oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl,oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl,carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and the like.

Particularly interesting aromatic heterocycles are pyrrolyl, furyl,thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl,isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl,benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, and the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom.

The terms carboxyl, carboxy or hydroxycarbonyl refer to a group —COOH.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhalomethyl as a group or part of agroup is defined as mono- or polyhalo-substituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₄alkyl or polyhaloC₁₋₆alkyl as a group orpart of a group is defined as mono- or polyhalosubstituted C₁₋₄alkyl orC₁₋₆alkyl, for example, the groups defined in halomethyl,1,1-difluoro-ethyl and the like. In case more than one halogen atoms areattached to an alkyl group within the definition of polyhalo-methyl,polyhaloC₁₋₄alkyl or polyhaloC₁₋₆alkyl, they may be the same ordifferent.

Whenever it occurs in the definition of the compounds of formula (I) orin any of the subgroups specified herein, each aryl independently is asdefined above in the definition of the compounds of formulas (I) or eacharyl can have any of the meanings specified hereinafter.

The term heterocycle in the definition of R⁷ or R^(7a) is meant toinclude all the possible isomeric forms of the heterocycles, forinstance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.

The carbocycle or heterocycle in the definition of R⁷ or R^(7a) may beattached to the remainder of the molecule of formula (I) through anyring carbon or heteroatom as appropriate, if not otherwise specified.Thus, for example, when the heterocycle is imidazolyl, it may be1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when thecarbocycle is naphthalenyl, it may be 1-naphthalenyl, 2-naphthalenyl andthe like.

When any variable (e.g. R⁷) occurs more than one time in anyconstituent, each definition of such variable is independent.

Any of the restrictions in the definitions of the radicals herein aremeant to be applicable to the group of compounds of formula (I) as wellas to any subgroup defined or mentioned herein.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counter ion is pharmaceutically acceptable. However, saltsof acids and bases which are non-pharmaceutically acceptable may alsofind use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acids as inorganic acids, for example, hydrohalic acids,e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;phosphoric acid and the like; or organic acids, for example, acetic,propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic,malonic, succinic, maleic, fumaric, malic, tartaric,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like. Conversely the salt form can be convertedby treatment with acid into the free acid form. The term addition saltalso comprises the hydrates and solvent addition forms which thecompounds of formula (I) are able to form. Examples of such forms aree.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of formula (I) andtheir N-oxides, addition salts, quaternary amines and stereochemicallyisomeric forms may contain one or more centers of chirality and exist asstereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) and their N-oxides, salts, solvates or quaternary aminessubstantially free, i.e. associated with less than 10%, preferably lessthan 5%, in particular less than 2% and most preferably less than 1% ofthe other isomers. Thus, when a compound of formula (I) is for instancespecified as (E), this means that the compound is substantially free ofthe (Z) isomer. In particular, stereogenic centers may have the R- orS-configuration; substituents on bivalent cyclic (partially) saturatedradicals may have either the cis- or trans-configuration. Compoundsencompassing double bonds can have an E (entgegen) or Z (zusammen)-stereochemistry at said double bond. The terms cis, trans, R, S, E andZ are well known to a person skilled in the art. Stereochemicallyisomeric forms of the compounds of formula (I) are intended to beembraced within the scope of this invention.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto also include their N-oxide forms, their salts, their quaternaryamines and their stereochemically isomeric forms. Of special interestare those compounds of formula (I), which are stereochemically pure.

Particular subgroups of compounds of formula (I) or any of the subgroupsof compounds of formula (I) specified herein which are thenon-salt-forms, the salts, the N-oxide forms and stereochemicallyisomeric forms. Of interest amongst these are the non-salt-forms, thesalts and stereochemically isomeric forms. As used herein, the term‘non-salt-form’ refers to the form of a compound which is not a salt,which in most cases will be the free base form.

It is to be understood that any of the subgroups of compounds offormulae (I) as defined herein, are meant to also comprise any prodrugs,N-oxides, addition salts, quaternary amines, metal complexes andstereochemically isomeric forms of such compounds.

Whenever mention is made hereinbefore or hereinafter that substituentscan be selected each independently out of a list of numerousdefinitions, such as for example for R⁹ and R¹⁰, all possiblecombinations are intended which are chemically possible or which lead tochemically stable molecules.

A number of subgroups of compounds of formula (I) are definedhereinafter. Further subgroups of compounds of formula (I) that formpart of the disclosure of this invention may comprise permutations ofany of the definitions used to specify the subgroups definedhereinafter.

Of interest are those compounds of formula (I), or any subgroup ofcompounds of formula (I) specified herein, wherein the compounds areother than 2-p-toluidino-6-methyl-9-p-toluyl-purine and2-p-phenetidino-6-methyl-9-p-ethoxyphenylpurine.

Of interest are those compounds of formula (I), or any subgroup ofcompounds of formula (I) specified herein, wherein R^(2a) is other thanmethyl or ethoxy; or wherein R^(2a) is other than C₁₋₂alkyl orC₁₋₂alkyloxy; R^(2a) is other than C₁₋₄alkyl or C₁₋₄alkyloxy; or whereinR^(2a) is other than C₁₋₆alkyl or C₁₋₆alkyloxy. Also of interest arethose compounds of formula (I), or any subgroup of compounds of formula(I) specified herein, wherein R³ is other than methyl or ethoxy; orwherein R³ is other than C₁₋₂alkyl or C₁₋₂alkyloxy; R^(2a) is other thanC₁₋₄alkyl or C₁₋₄alkyloxy; or wherein R³ is other than C₁₋₆alkyl orC₁₋₆alkyloxy. Also of interest are those compounds of formula (I), orany subgroup of compounds of formula (I) specified herein, whereinR^(2a) and R³ is other than methyl or ethoxy; or wherein R^(2a) and R³are other than C₁₋₂alkyl or C₁₋₂alkyloxy; or wherein R^(2a) and R³ areother than C₁₋₄alkyl or C₁₋₄alkyloxy; or wherein R^(2a) and R³ are otherthan C₁₋₆alkyl or C₁₋₆alkyloxy.

Particular subgroups of the compounds of formula (I) are those compoundsof formula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein -a¹=a²-a³=a⁴- is —CH═CH—CH═CH— (a-1).

Further subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein -b¹=b²-b³=b⁴- is —CH═CH—CH═CH— (b-1).

Further subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein (a) n is 0, 1, 2, 3; or wherein (b) n is 0, 1 or 2; or(c) n is 0.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein (a) m is 0, 1, 2, 3; or wherein (b) m is 0, 1 or 2; or(c) m is 2.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R¹ is hydrogen; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; or-   (b) R¹ is hydrogen; C₁₋₆alkyl; or-   (c) R¹ is hydrogen.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R² is hydroxy; halo; C₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano and —C(═O)R⁶; C₃₋₇cycloalkyl;    C₂₋₆alkenyl optionally substituted with one substituent selected    from halo, cyano and —C(═O)R⁶; C₂₋₆alkynyl optionally substituted    with one substituent selected from halo, cyano and —C(═O)R⁶;    C₁₋₆alkyl-oxycarbonyl; carboxyl; cyano; nitro; amino; mono- or    di(C₁₋₆alkyl)amino; polyhalomethyl; polyhalomethylthio;    —S(═O)_(p)R⁶; —NH—S(═O)_(p)R⁶; —C(═O)R⁶; —NHC(═O)H; —C(═O)NHNH₂;    NHC(═O)R⁶; C(═NH)R⁶;-   (b) R² is hydroxy; halo; C₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano and —C(═O)R⁶; C₂₋₆alkenyl    optionally substituted with one substituent selected from halo,    cyano and —C(═O)R⁶; C₂₋₆alkynyl optionally substituted with one    substituent selected from halo, cyano and —C(═O)R⁶;    C₁₋₆alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or    di(C₁₋₆alkyl)amino; trifluoromethyl;-   (c) R² is halo, C₁₋₆alkyl optionally substituted with cyano,    C₂₋₆alkenyl optionally substituted with cyano, C₂₋₆alkynyl    optionally substituted with cyano, C₁₋₆alkyloxy-carbonyl, carboxyl,    cyano, amino, mono(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino;-   (d) R² is halo, cyano, aminocarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyl,    C₁₋₆alkyl substituted with cyano or C₂₋₆alkenyl substituted with    cyano;-   (e) R² is halo, cyano, aminocarbonyl, C₁₋₄alkyl substituted with    cyano or C₂₋₄alkenyl substituted with cyano;-   (f) R² is cyano, aminocarbonyl; or (g) R² is cyano.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R^(2a) is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo;    C₁₋₆alkyloxy wherein C₁₋₆alkyl may optionally be substituted with    cyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₁₋₆alkyl substituted with hydroxy and a second substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkenyl substituted with one    substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl substituted with one    substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X—R⁷;-   (b) R^(2a) is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo;    C₁₋₆alkyloxy wherein C₁₋₆alkyl may optionally be substituted with    cyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₂₋₆alkenyl    substituted with one substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₂₋₆alkynyl substituted with one substituent selected    from halo, cyano, —C(═O)—NR⁹R¹⁰;-   (c) R^(2a) is halo, cyano, aminocarbonyl, C₁₋₆alkyl optionally    substituted with cyano or aminocarbonyl, C₂₋₆alkenyl optionally    substituted with cyano or aminocarbonyl;-   (d) R^(2a) is halo, cyano, aminocarbonyl, C₁₋₆alkyl substituted with    cyano or aminocarbonyl, or C₂₋₆alkenyl substituted with cyano or    aminocarbonyl;-   (e) R^(2a) is cyano, aminocarbonyl, C₁₋₆alkyl substituted with cyano    or C₂₋₆alkenyl substituted with cyano;-   (f) R^(2a) is cyano, aminocarbonyl, C₁₋₄alkyl substituted with cyano    or C₂₋₄alkenyl substituted with cyano;-   (g) R^(2a) is cyano, C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano; or-   (h) R^(2a) is cyano.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) -A-B— represents a bivalent radical of formula    —CR⁵═N—  (c-1);    —N═N—  (c-2);    —CH₂—CH₂—  (c-3);    —CH═CH—  (c-6);-   (b) -A-B— represents a bivalent radical of formula    —CR⁵═N—  (c-1);-   (c) -A-B— represents a bivalent radical of formula    —N═N—  (c-2);-   (d) -A-B— represents a bivalent radical of formula    —CH₂—CH₂—  (c-3);-   (e) -A-B— represents a bivalent radical of formula    —CS—NH—  (c-4);-   (f) -A-B— represents a bivalent radical of formula    —CO—NH—  (c-5);-   (g) -A-B— represents a bivalent radical of formula    —CH═CH—  (c-6);-   (h) -A-B— represents a bivalent radical of formula —CH═N—.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R³ is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₁₋₆alkyl substituted with hydroxy and a second substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkenyl substituted with one    substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl substituted with one    substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X—R⁷;-   (b) R³ is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₂₋₆alkenyl    substituted with one substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₂₋₆alkynyl substituted with one substituent selected    from halo, cyano, —C(═O)—NR⁹R¹⁰;-   (c) R³ is halo, cyano, aminocarbonyl, C₁₋₆alkyl optionally    substituted with cyano or aminocarbonyl, C₂₋₆alkenyl optionally    substituted with cyano or aminocarbonyl;-   (d) R³ is halo, cyano, aminocarbonyl, C₁₋₆alkyl substituted with    cyano or amino-carbonyl, or C₂₋₆alkenyl substituted with cyano or    aminocarbonyl;-   (e) R³ is cyano, C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (f) R³ is C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (g) R³ is C₂₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (h) R³ is C₂₋₄alkenyl substituted with cyano;-   (i) R³ is ethenyl substituted with cyano;-   (j) R³ is (E)-2-cyanoethenyl.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R⁴ is halo; hydroxy; C₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano or —C(═O)R⁶; C₂₋₆alkenyl    optionally substituted with one substituent selected from halo,    cyano or —C(═O)R⁶; C₂₋₆alkynyl optionally substituted with one    substituent selected from halo, cyano or —C(═O)R⁶; C₃₋₇cycloalkyl;    C₁₋₆alkyloxy; cyano; nitro; polyhaloC₁₋₆alkyl; polyhaloC₁₋₆alkyloxy;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl; formyl; amino; mono- or    di(C₁₋₄alkyl)amino or R⁷;-   (b) R⁴ is halo; hydroxy; C₁₋₆alkyl optionally substituted with one    substituent selected from cyano; C₂₋₆alkenyl optionally substituted    with cyano; C₂₋₆alkynyl optionally substituted with cyano;    C₃₋₇cycloalkyl; C₁₋₆alkyloxy; cyano; nitro; trifluoromethyl;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl; formyl; amino; mono- or    di(C₁₋₄alkyl)amino and R⁷;-   (c) R⁴ is halo; hydroxy; C₁₋₆alkyl optionally substituted with    cyano; C₂₋₆alkenyl optionally substituted with cyano; C₂₋₆alkynyl    optionally substituted with cyano; C₁₋₆alkyloxy; cyano; nitro;    trifluoromethyl; aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl; formyl; amino; mono- or    di(C₁₋₄alkyl)amino;-   (d) R⁴ is halo, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    C₁₋₆alkyloxy, cyano, nitro, amino;-   (e) R⁴ is halo, hydroxy, C₁₋₄alkyloxy, cyano; or (f) R⁴ is halo,    C₁₋₄alkyl, C₁₋₄alkyloxy.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R⁵ is hydrogen, C₁₋₆alkyl, aryl, pyridyl, thienyl, furanyl;-   (b) R⁵ is hydrogen, C₁₋₆alkyl, aryl, pyridyl, furanyl; wherein aryl    in (a) or (b) may have the meanings defined hereinabove or    hereinafter.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) Q is hydrogen, C₁₋₆alkyl or —NR⁹R¹⁰;-   (b) Q is hydrogen or —NR⁹R¹⁰;-   (c) Q is hydrogen, amino, mono- or di-C₁₋₄alkylamino; (d) Q is    hydrogen or C₁₋₆alkyl; or-   (d) Q is hydrogen.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) R⁶ is C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino; in    particular-   (b) R⁶ is C₁₋₄alkyl or amino; or-   (c) R⁶ is C₁₋₄alkyl.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R⁷ is a monocyclic or bicyclic, partially saturated or aromatic    carbocycle or a monocyclic or bicyclic, partially saturated or    aromatic heterocycle, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    and aminocarbonyl; in particular-   (b) R⁷ is any of the specific monocyclic or bicyclic, partially    saturated or aromatic carbocycles or monocyclic or bicyclic,    partially saturated or aromatic heterocycles specifically mentioned    in this specification, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxy-carbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    and aminocarbonyl;-   (c) R^(7a) is a monocyclic or bicyclic, partially saturated or    aromatic carbocycle or a monocyclic or bicyclic, partially saturated    or aromatic heterocycle, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    and aminocarbonyl; in particular-   (d) R^(7a) is any of the specific monocyclic or bicyclic, partially    saturated or aromatic carbocycles or monocyclic or bicyclic,    partially saturated or aromatic heterocycles specifically mentioned    in this specification, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxy-carbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    and aminocarbonyl.

Further subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) X is —NR¹—, —O— or —S—;-   (b) (b) X is —NR¹ — or —O—;-   (c) (c) X is —NH—, —N(C₁₋₄alkyl)—, —O—;-   (d) X is —NH—, —N(CH₃)—, —O—; or (e) X is —NH—, —O—.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein (a) R⁸ is hydrogen, C₁₋₄alkyl or arylC₁₋₄alkyl; or (b)R⁸ is hydrogen or C₁₋₄alkyl; or (c) R⁸ is hydrogen or methyl.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) R⁹ and R¹⁰ each independently are hydrogen; C₁₋₆alkyl;    C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; —CH(═NR¹¹), wherein each of the    aforementioned C₁₋₆alkyl groups may optionally be substituted with    one or two substituents each independently selected from hydroxy,    C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,    cyano, amino, mono- and di(C₁₋₄alkyl)amino, polyhalomethyl,    polyhalomethyloxy;-   (b) R⁹ and R¹⁰ each independently are hydrogen; C₁₋₆alkyl;    C₁₋₆alkylcarbonyl or C₁₋₆alkyloxycarbonyl;-   (c) R⁹ and R¹⁰ each independently are hydrogen or C₁₋₆alkyl;-   (d) R⁹ and R¹⁰ are hydrogen.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R¹³ and R¹⁴ each independently are C₁₋₆alkyl optionally    substituted with cyano, C₂₋₆alkenyl optionally substituted with    cyano, C₂₋₆alkynyl optionally substituted with cyano;-   (b) R¹³ and R¹⁴ each independently are hydrogen or C₁₋₆alkyl;-   (c) R¹³ and R¹⁴ are hydrogen.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein R¹⁵ is C₁₋₆alkyl optionally substituted withcyano.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein (a) R¹⁶ is C₁₋₆alkyl optionally substitutedwith cyano or aminocarbonyl; or wherein (b) R¹⁶ is C₁₋₆alkyl optionallysubstituted with cyano.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cyclo-alkyl,    C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,    polyhalo-C₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, phenyl,    thienyl and pyridyl;-   (b) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxy C₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)amino C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro, trifluoromethyl,    trifluoromethoxy, aminocarbonyl, phenyl;-   (c) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)amino C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, cyano, nitro, trifluoromethyl;-   (d) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro, trifluoromethyl.

One embodiment concerns a subgroup of compounds of formula (I) havingthe formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein -b¹=b²-b³=b⁴-, R¹, each R², R^(2a), R³, each R⁴, -A-B—, m, n andQ are as defined hereinabove in the general definition of the compoundsof formula (I) or in the various subgroups thereof.

Yet another embodiment concerns a subgroup of compounds of formula (I)having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein -a¹=a²-a³=a⁴-, R¹, each R², R^(2a), R³, each R⁴, -A-B—, m, n andQ are as defined hereinabove in the general definition of the compoundsof formula (I) or in the various subgroups thereof.

Another embodiment concerns a subgroup of compounds of formula (I)having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein R¹, each R², R^(2a), R³, each R⁴, -A-B—, m, n and Q are asdefined hereinabove in the general definition of the compounds offormula (I) or in the various subgroups thereof.

A further embodiment concerns a subgroup of compounds of formula (I)having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein R¹, R^(2a), R³, each R⁴, -A-B— and Q are as defined hereinabovein the general definition of the compounds of formula (I) or in thevarious subgroups thereof.

Also an interesting embodiment concerns a subgroup of compounds offormula (I) having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein R¹, R², R^(2a), R³, -A-B— and Q are as defined hereinabove inthe general definition of the compounds of formula (I) or in the varioussubgroups thereof.

Particular subgroups of compounds of formula (I), (I′), (I″), (I′″),(I″″) or (I′″″) are those wherein -A-B— is a radical —CR⁵═N— (c-1),wherein R^(2a) has the meanings specified in (a)-(i), and R³ has themeanings specified in (j)-(t), as follows:

-   (a) R^(2a) is cyano; aminocarbonyl; amino; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl is substituted with cyano; NHR¹³; NR¹³R¹⁴;    —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴—C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶;    C₁₋₆alkyl substituted with one, two or three substituents each    independently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with hydroxy and a    second substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally    substituted with one, two or three substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₂₋₆alkenyl substituted with one, two or three substituents    each independently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl substituted with one, two or    three substituents each independently selected from halo, cyano,    NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷;    —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X—R⁷;-   (b) R^(2a) is cyano; aminocarbonyl; amino; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl is substituted with cyano; NHR¹³; NR¹³R¹⁴;    —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶;    C₁₋₆alkyl substituted with one substituent selected from halo,    cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyl    substituted with hydroxy and a second substituent selected from    halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;    C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₂₋₆alkenyl substituted with one substituent selected from    halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷;    C₂₋₆alkynyl substituted with one substituent selected from halo,    cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷;    —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X—R⁷;-   (c) R^(2a) is cyano; aminocarbonyl; amino; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl is substituted with cyano; NHR¹³; NR¹³R¹⁴;    —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶;    C₁₋₆alkyl substituted with one substituent selected from halo,    cyano, —C(═O)—NR⁹R¹⁰; C₁₋₆alkyl substituted with hydroxy and a    second substituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰;    C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one substituent    selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₂₋₆alkenyl substituted    with one substituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰;    C₂₋₆alkynyl substituted with one substituent selected from halo,    cyano, —C(═O)—NR⁹R¹⁰;-   (d) R^(2a) is halo, cyano, aminocarbonyl, C₁₋₆alkyl substituted with    cyano or aminocarbonyl, C₂₋₆alkenyl optionally substituted with    cyano or aminocarbonyl;-   (e) R^(2a) is halo, cyano, aminocarbonyl, C₁₋₆alkyl substituted with    cyano or aminocarbonyl, or C₂₋₆alkenyl substituted with cyano or    aminocarbonyl;-   (f) R^(2a) is cyano, aminocarbonyl, C₁₋₆alkyl substituted with cyano    or C₂₋₆alkenyl substituted with cyano;-   (g) R^(2a) is cyano, aminocarbonyl, C₁₋₄alkyl substituted with cyano    or C₂₋₄alkenyl substituted with cyano;-   (h) R^(2a) is cyano, C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano; or-   (i) R^(2a) is cyano;-   (j) R³ is cyano; aminocarbonyl; amino; halo; C₁₋₆alkyloxy wherein    C₁₋₆alkyl is substituted with cyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³;    —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl    substituted with one, two or three substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₁₋₆alkyl substituted with hydroxy and a second substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one, two    or three substituents each independently selected from halo, cyano,    NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkenyl    substituted with one, two or three substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    and R⁷; C₂₋₆alkynyl substituted with one, two or three substituents    each independently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl or R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ and —X—R⁷.-   (k) R³ is cyano; aminocarbonyl; amino; halo; C₁₋₆alkyloxy wherein    C₁₋₆alkyl is substituted with cyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³;    —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl    substituted with one substituent selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyloxyC₁₋₆alkyl    optionally substituted with one substituent selected from halo,    cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkenyl    substituted with one substituent selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl substituted with    one substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl and R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X—R⁷;-   (l) R³ is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₂₋₆alkenyl    substituted with one substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₂₋₆alkynyl substituted with one substituent selected    from halo, cyano, —C(═O)—NR⁹R¹⁰;-   (m) R³ is halo, cyano, aminocarbonyl, C₁₋₆alkyl optionally    substituted with cyano or aminocarbonyl, C₂₋₆alkenyl optionally    substituted with cyano or aminocarbonyl;-   (n) R³ is halo, cyano, aminocarbonyl, C₁₋₆alkyl substituted with    cyano or aminocarbonyl, or C₂₋₆alkenyl substituted with cyano or    aminocarbonyl;-   (o) R³ is cyano, C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (p) R³ is C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (q) R³ is C₂₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (r) R³ is C₂₋₄alkenyl substituted with cyano;-   (s) R³ is ethenyl substituted with cyano;-   (t) R³ is (E)-2-cyanoethenyl.

Particular subgroups of compounds of formula (I), (I′), (I″), (I′″),(I″″) or (I′″″) are those wherein -A-B— is a radical —N═N— (c-2), orwherein -A-B— is a radical of formula —CH₂—CH₂— (c-3); and wherein

-   (a) R³ is C₁₋₆alkyl substituted with cyano or aminocarbonyl, or    C₂₋₆alkenyl substituted with cyano or aminocarbonyl;-   (b) R³ is C₂₋₆alkyl substituted with cyano or aminocarbonyl, or    C₂₋₆alkenyl substituted with cyano or aminocarbonyl;-   (c) R³ is C₂₋₄alkyl substituted with cyano or aminocarbonyl, or    C₂₋₄alkenyl substituted with cyano or aminocarbonyl;-   (d) R³ is C₂₋₆alkyl substituted with cyano, or C₂₋₆alkenyl    substituted with cyano;-   (e) R³ is C₂₋₄alkyl substituted with cyano, or C₂₋₄alkenyl    substituted with cyano;-   (f) R³ is C₂₋₆alkenyl substituted with cyano or aminocarbonyl;-   (g) R³ is C₂₋₄alkenyl substituted with cyano or aminocarbonyl;-   (h) R³ is C₂₋₆alkenyl substituted with cyano;-   (i) R³ is C₂₋₆alkenyl substituted with cyano;-   (j) R³ is ethenyl substituted with cyano; or wherein-   (k) R³ is (E)-2-cyanoethenyl.

Particular subgroups of compounds of formula (I), (I′), (I″), (I′″),(I″″) or (I′″″) are those wherein -A-B— is a radical —N═N— (c-2), orwherein -A-B— is a radical of formula —CH₂—CH₂— (c-3); and wherein

-   (a) R^(2a) is cyano or aminocarbonyl; or wherein-   (b) R^(2a) is cyano.

Particular subgroups of compounds of formula (I), (I′), (I″), (I′″),(I″″) or (I′″″) are those wherein -A-B— is a radical —N═N— (c-2), orwherein -A-B— is a radical of formula —CH₂—CH₂— (c-3); and wherein

-   (a) R³ is C₁₋₆alkyl substituted with cyano or aminocarbonyl, or    C₂₋₆alkenyl substituted with cyano or aminocarbonyl;-   (b) R³ is C₂₋₆alkyl substituted with cyano or aminocarbonyl, or    C₂₋₆alkenyl substituted with cyano or aminocarbonyl;-   (c) R³ is C₂₋₄alkyl substituted with cyano or aminocarbonyl, or    C₂₋₄alkenyl substituted with cyano or aminocarbonyl;-   (d) R³ is C₂₋₆alkyl substituted with cyano, or C₂₋₆alkenyl    substituted with cyano;-   (e) R³ is C₂₋₄alkyl substituted with cyano, or C₂₋₄alkenyl    substituted with cyano;-   (f) R³ is C₂₋₆alkenyl substituted with cyano or aminocarbonyl;-   (g) R³ is C₂₋₄alkenyl substituted with cyano or aminocarbonyl;-   (h) R³ is C₂₋₆alkenyl substituted with cyano;-   (i) R³ is C₂₋₆alkenyl substituted with cyano;-   (j) R³ is ethenyl substituted with cyano; or wherein-   (k) R³ is (E)-2-cyanoethenyl;-   and for each of the possibilities (a)-(k), R^(2a) is cyano or    aminocarbonyl; or R^(2a) is cyano.

The compounds of formula (I) can be prepared by reacting an intermediateof formula (II-a) or (II-b) with an intermediate of formula (III-a) or(III-b). In this and the following reaction schemes each W independentlyrepresents a suitable leaving group, such as for example halogen, e.g.chloro, bromo, iodo, an acetate group, a nitrobenzoate group, an azidegroup, an arylsulfonyl group, e.g. tosylate, brosylate, mesylate,nosylate, triflate, and the like. Of particular interest are halogroups, in particular chloro or bromo.

The reaction of the pyrimidine derivative (II-a) respectively (II-b)with the amine (III-a) respectively the intermediate (III-b) istypically conducted in a suitable solvent. Suitable solvents are forexample an alcohol, such as for example ethanol, 2-propanol; a dipolaraprotic solvent such as acetonitrile, N,N-dimethylformamide;N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone; an ether such astetrahydrofuran, 1,4-dioxane, propylene glycol monomethylether. Thesereactions can be conducted under neutral conditions or, which ispreferred, at acidic conditions, usually at elevated temperatures andunder stirring. The acid conditions may be obtained by adding amounts ofa suitable acid e.g. camphor sulfonic acid or by using acid solvents,e.g. hydrochloric acid or in an alkanol such as 1- or 2-propanol, or anether such as tetrahydrofuran.

The compounds of formula (I) can also be prepared by reacting thebicyclic derivative (IV) with (V) as outlined in the following scheme.

In this reaction scheme W represents an appropriate leaving group asspecified above. The reaction is conducted using similar reactionconditions as outlined above for the reactions of (II-a) with (III-a)and (II-b) with (III-b).

The compounds of formula (I-a) which are compounds of formula (I)wherein -A-B— is —CH₂—CH₂— can be prepared by reacting a pyrimidinederivative (VI) wherein each W is a leaving group as specified above andpreferably is chloro or bromo, with an aromatic amine of formula (VII).

The compounds of formula (I-a) can be converted to the correspondingcompounds (I-b) which are compounds of formula (I) wherein -A-B— is—CH═CH—, by an elimination reaction, in particular by eliminatinghydrogen from a corresponding saturated analog (I-a), using anappropriate dehydrogenating reagent such as, e.g.,2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

The compounds of formula (I-c) which are compounds of formula (I)wherein -A-B— is —CR⁵═N— can be prepared by reacting an aminopyrimidine(VIII) with an orthoformate R⁵C(OEt)₃ or with an aldehyde R⁵CH═O in thepresence of a mild oxidant such as nitrobenzene.

The compounds of formula (I-c-1) which are compounds of formula (I)wherein -A-B— is —CR⁵═N— wherein R⁵ is amino can be prepared by reactingan aminopyrimidine (VIII) with a cyanogen halide, in particular withcyanogen bromide. This reaction may be conducted in a suitable solventsuch as an alcohol, e.g. methanol, ethanol, or an ether, e.g. THF ordioxane, or mixtures thereof.

The compounds of formula (I-c-1) can be mono- or bis-alkylated to thecorresponding compounds wherein R⁵ is mono- or di(C₁₋₄alkyl)amino usinga reagent C₁₋₄alkyl-W as alkylating agent.

The compounds of formula (I-d), which are compounds of formula (I)wherein -A-B— is —N═N—, can be prepared by reacting an aminopyrimidine(VIII) with a diazo-forming reagent such as a nitrite, in particular analkali metal nitrite, e.g. sodium or potassium nitrite in the presenceof acetic acid.

The compounds of formula (I-e) or (I-f) which are compounds of formula(I) wherein -A-B— is —CS—NH— or, respectively, —CO—NH—, can be preparedby reacting an aminopyrimidine (VIII) with a thiophosgene derivative(W¹)₂C═S, yielding compounds (I-e) or with a phosgene derivative(W¹)₂C═S, yielding compounds (I-f). In these reaction schemes, each W¹independently represents a leaving group such as the groups W specifiedabove, preferably W¹ is halo, in particular chloro.

In any of the above or the following reaction schemes each of theradicals R², R^(2a), R³ or R⁴ may be as defined above or may also be aprecursor group, which is converted to the desired R², R^(2a), R³ or R⁴group. For example, the compounds of formula (I) wherein R³ isC₂₋₆alkenyl substituted with one, two or three substituents eachindependently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,—C(═O)—C₁₋₆alkyl or R⁷, may be prepared starting from the analogs ofthese compounds wherein R³ is an ester group such as aC₁₋₆alkyloxycarbonyl group, which is reduced to a hydroxymethylenegroup, e.g. with a complex metal hydride such as lithium aluminumhydride, which subsequently is oxidized to an aldehyde group using amild oxidant (for example MnO₂). The aldehyde group is then convertedinto an alkenyl or substituted alkenyl group using a Wittig reaction ora Wittig-Horner reaction. In the former instance a Wittig type reagent,such as a triphenyl-phosphoniumylide is used. The Wittig conversion isconducted in a suitable reaction-inert solvent such as an ether,starting from triphenylphosphine and e.g. a halo acetonitrile (e.g.chloroacetonitrile) or a halo acetic acid ester of formulaR^(x)—CH(Halo)-COOR^(y), wherein R^(x) and R^(y) independently areC₁₋₆alkyl, C₁₋₄alkyl or C₁₋₂alkyl groups. The Wittig-Horner reaction isperformed using a phosphonate, such as e.g. a reagent of formuladi(C₁₋₆alkyl-oxy)-P (═O)—CH(R^(x))—COOR^(y) ordi(C₁₋₆alkyloxy)-P(═O)—CH(R^(x))—CN in the presence of a base,preferably a strong base, e.g. an alkali metal alkoxide such as sodiumor potassium methoxide, ethoxide, t.butyloxide, in an ether, e.g THF ordioxane, an aprotic organic solvent, e.g. DMF, DMA, HMPT, DMSO and thelike. A similar reaction sequence may be followed for those compounds offormula (I) wherein R², R^(2a) or R⁴ is a substituted C₂₋₆alkenyl groupas specified above.

Any of the conversions of the intermediates as described hereinafter canalso be applied on analogs of the compounds of formula (I) wherein R²,R^(2a), R³ or R⁴ is a precursor group. For example, the reaction of(III-b) or (V-b) with (XIII) to yield (III-c) or (V-c), of (III-f) to(III-c), of (V-f) to (V-c), of (III-b) to (III-f) etc., all thesereactions being described hereinafter in more detail, may also beapplied to analogs of the starting materials wherein the —NHR¹ group isa group

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a tertiarynitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I) wherein R², R^(2a), R³ or R⁴ is C₂₋₆alkenylsubstituted with aminocarbonyl, can be converted into a compound offormula (I) wherein R², R^(2a), R³ or R⁴ is C₂₋₆alkenyl substituted withcyano by reaction with POCl₃.

Compounds of formula (I) wherein m is zero, can be converted into acompound of formula (I) wherein m is other than zero and R⁴ representshalo, by reaction with a suitable halo-introducing agent, such as forexample N-chlorosuccinimide or N-bromo-succinimide, or a combinationthereof, in the presence of a suitable solvent, such as for exampleacetic acid.

Compounds of formula (I) wherein R³ represents halo, may be convertedinto a compound of formula (I) wherein R³ represents C₂₋₆alkenylsubstituted with one or more substituents each independently selectedfrom halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷, byreaction with the corresponding C₂₋₆alkene substituted with one or moresubstituents each independently selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ in the presence of a suitablebase, such as for example N,N-diethylethanamine, a suitable catalyst,such as for example palladium acetate in the presence oftriphenylphosphine, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R^(2a) represents halo, may beconverted into a compound of formula (I) wherein R^(2a) representsC₂₋₆alkenyl substituted with one or more substituents each independentlyselected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl orR⁷, by reaction with the corresponding C₂₋₆alkene substituted with oneor more substituents each independently selected from halo, cyano,NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ in the presence of asuitable base, such as for example N,N-diethyl-ethanamine, a suitablecatalyst, such as for example palladium acetate in the presence oftriphenylphosphine, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyloxycarbonyl, canbe converted into a compound of formula (I) wherein R¹ representshydrogen, by reaction with a suitable base, such as for example sodiumhydroxide or methoxide. Where R¹ is t.butyloxycarbonyl, thecorresponding compounds wherein R¹ is hydrogen can be made by treatmentwith trifluoroacetic acid.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be available commercially or may be prepared according to art-knownprocedures.

Intermediates of formula (II-a) can be prepared as outlined in thefollowing reaction scheme. In this scheme W represents a suitableleaving group, such as the W groups specified above, or a precursor of aleaving group that can conveniently be converted into a leaving group,e.g. a hydroxy function or a protected hydroxy function, by reactionwith a halogenating agent. B¹ represents a precursor of B such as anamino group or a group —CH₂—CH₂—W. The -A-B-linking agent can be any ofthe agents mentioned above in the preparation of compounds (I-a), (I-c),(I-d), (I-e) and (I-f). The same or similar reaction conditions asdescribed for the preparation of the latter compounds can also be usedin the preparation of (II-a).

In a similar manner, intermediates (II-b) can be prepared starting froma pyrimidine (X) as outlined in the following scheme:

In the above reaction the amino group may or may not be protected by asuitable protective group, e.g., an acetyl, trifluoroacetyl, benzyl,butyloxycarbonyl, benzyloxycarbonyl and the like N-protecting groups.

Intermediates of formula (III-a) wherein R¹ is hydrogen, saidintermediates being represented by formula (III-a′), or intermediates offormula (VII), can be prepared by reacting intermediates of formula (XI)or (XII) with a suitable reducing agent, such as Fe, in the presence ofNH₄Cl and a suitable solvent, such as for example tetrahydrofuran, H₂Oand an alcohol, e.g. methanol and the like. The intermediates of formula(III-a′) can be converted to intermediates of formula (III-a) wherein R¹is other than hydrogen, by an N-alkylation reaction with a reagent R¹—W,wherein W is as specified above.

Intermediates of formula (III-b) or (V) are either commerciallyavailable or can be prepared in a straightforward manner, e.g. byconverting corresponding intermediates having a hydroxy function into agroup W, e.g. by reaction with a halogenating agent (e.g. POCl₃, SOCl₂,PCl₃ and the like).

Intermediates of formula (III-a) wherein R^(2a) represents C₂₋₆alkylsubstituted with cyano and R¹ is hydrogen, said intermediates beingrepresented by formula (III-a-1), can be prepared by reacting anintermediate of formula (XI-a) with Pd/C in the presence of a suitablesolvent, such as for example an alcohol, e.g. ethanol and the like.Similarly, intermediates of formula (XII-a) may be converted tointermediates of formula (VII-a), which are intermediates of formula(VII) wherein R^(2a) represents C₂₋₆alkyl substituted with cyano.

Intermediates of formula (III-a) or (VII) wherein R^(2a) or R³ is halo,said intermediates being represented by formula (III-a-2) and (VII-b),may be converted into intermediates of formula (III-a-3) and (VII-c)respectively, wherein R^(2a) respectively R³ is C₂₋₆alkenyl substitutedwith C(═O)NR⁹R¹⁰, by reacting the starting intermediates with anintermediate of formula (XIII) in the presence of Pd(OAc)₂, P(o-Tol)₃, asuitable base, e.g. N,N-diethylethanamine, and a suitable solvent, suchas for example CH₃CN.

Intermediates of formula (III-a-3) and (VII-c) can also be prepared byreacting intermediates of formula (III-a-4) or (VII-d) with H—NR⁹R¹⁰ inthe presence of oxalyl chloride and in the presence of a suitablesolvent, such as for example N,N-dimethyl-formamide, CH₂Cl₂ andtetrahydrofuran.

Intermediates of formula (III-a-4) and (VII-d) can be prepared byreacting intermediates of formula (III-a-2) and (VII-b), withH—C₂₋₆alkenyl-C(═O)—OH in the presence of to Pd(OAc)₂, P(o-Tol)₃, asuitable base, such as for example N,N-diethylethanamine, and a suitablesolvent, such as for example CH₃—CN.

Intermediates of formula (III-a-2) and (VII-b) may also be convertedinto intermediates of formula (III-a) or (VII) wherein R^(2a)respectively R³ is C₂₋₆alkenyl substituted with CN, said intermediatesbeing represented by formula (III-a-5) and (VII-e) by reaction withH—C₂₋₆alkenyl-CN in the presence of Pd(OAc)₂, P(o-Tol)₃, a suitablebase, such as for example N,N-diethylethanamine, and a suitable solvent,such as for example CH₃—CN.

Intermediates of formula (XIII) can be prepared by reacting anintermediate of formula (XIII′) wherein W represents a suitable leavinggroup, such as defined above and in particular is halogen, e.g. chloro,with H—NR⁹R¹⁰ in the presence of a suitable solvent, such as for examplediethylether and tetrahydrofuran.H—C₂₋₆alkenyl-C(═O)—W+H—NR⁹R¹⁰→  (XIII′)H—C₂₋₆alkenyl-C(═O)—NR⁹R¹⁰   (XIII)

Intermediates of formula (XI) or (XII) wherein R^(2a) respectively R³represents cyanovinyl, said intermediates being represented by formula(XI-a) and (XII-a), can be prepared by reacting an intermediate offormula (XV) respectively (XVI) with diethylcyanomethyl-phosphonate inthe presence of a suitable base, such as for example NaOCH₃, and asuitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (XI) or (XII) wherein R^(2a) respectively R³ torepresents —C(CH₃)═CH—CN, said intermediates being represented byformula (XI-b) and (XII-b), can be prepared by reacting an intermediateof formula (XV′) respectively (XVI′) with diethylcyanomethylphosphonatein the presence of a suitable base, such as for example NaOCH₃, and asuitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (XV) and (XVI) can be prepared by reacting anintermediate of formula (XVII) respectively (XVIII) with a suitableoxidizing agent, such as for example MnO₂, in the presence of a suitablesolvent, such as for example a ketone, e.g. acetone, an ether, e.g. THFor dioxane, a halogenated hydrocarbon, e.g. dichloromethane orchloroform.

Intermediates of formula (XVII) and (XVIII) can be prepared by reactingan intermediate of formula (XIX) respectively (XX) with NaBH₄ in thepresence of ethylchloroformate, a suitable base, such as for exampleN,N-diethylethanamine, and a suitable solvent, such as for exampletetrahydrofuran.

Intermediates of formula (XI) and (XII) wherein R^(2a) respectively R³represent hydroxy, said intermediates being represented by formula(XI-c) respectively (XII-c), can be converted into an intermediate offormula (XI) respectively (XII) wherein R^(2a) respectively R³ representC₁₋₆alkyloxy wherein the C₁₋₆alkyl may optionally be substituted withcyano, said R^(2a) respectively R³ being represented by P and saidintermediates being represented by formula (XI-d) respectively (XII-d),by reaction with an intermediate of formula (XXI) wherein W represents asuitable leaving group, such as the leaving groups mentioned above, andin particular is halogen, e.g. chloro and the like, optionally in thepresence of a catalyst such as an alkali metal iodide, e.g. NaI or KI,and further optionally in the presence of a suitable base, such as forexample an alkali metal carbonate, e.g. K₂CO₃, and a suitable solvent,such as for example a ketone, e.g. acetone, an ether, e.g. THF, dioxane,a halogenated hydrocarbon, e.g. chloroform, dichloromethane.

Intermediates of formula (XI) and (XII) can be prepared by reacting anintermediate of formula (XXII) respectively (XXIII) with NaNO₃ in thepresence of CH₃SO₃H.

Intermediates of formula (IV) can be prepared by reacting anintermediate of formula (XXIV) wherein W is as specified above, with(III-a):

The intermediates (XXIV) are either commercially available or can beprepared by using an -A-B-linking agent as described above in thereactions of (IX) to (II-a) and (X) to (II-b).

The compounds of formula (I) show antiretroviral properties (reversetranscriptase to inhibiting properties), in particular against HumanImmunodeficiency Virus (HIV), which is the aetiological agent ofAcquired Immune Deficiency Syndrome (AIDS) in humans. The HIV viruspreferentially infects human T-4 cells and destroys them or changestheir normal function, particularly the coordination of the immunesystem. As a result, an infected patient has an ever decreasing numberof T-4 cells, which moreover behave abnormally. Hence, the immunologicaldefense system is unable to combat infections and neoplasms and the HIVinfected subject usually dies by opportunistic infections such aspneumonia, or by cancers. Other conditions associated with HIV infectioninclude thrombocytopaenia, Kaposi's sarcoma and infection of the centralnervous system characterized by progressive demyelination, resulting indementia and symptoms such as, progressive dysarthria, ataxia anddisorientation. HIV infection further has also been associated withperipheral neuropathy, progressive generalized lymphadenopathy (PGL) andAIDS-related complex (ARC).

The present compounds also show activity against (multi) drug resistantHIV strains, in particular (multi) drug resistant HIV-1 strains, more inparticular the present compounds show activity against HIV strains,especially HIV-1 strains, that have acquired resistance to one or moreart-known non-nucleoside reverse transcriptase inhibitors. Art-knownnon-nucleoside reverse transcriptase inhibitors are those non-nucleosidereverse transcriptase inhibitors other than the present compounds andknown to the person skilled in the art, in particular commercialnon-nucleoside reverse transcriptase inhibitors. The present compoundsalso have little or no binding affinity to human α-1 acid glycoprotein;human α-1 acid glycoprotein does not or only weakly affect the anti HIVactivity of the present compounds.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I), their N-oxides, pharmaceutically acceptable addition salts,quaternary amines and stereochemically isomeric forms thereof, areuseful in the treatment of individuals infected by HIV and for theprophylaxis of these infections. In general, the compounds of thepresent invention may be useful in the treatment of warm-blooded animalsinfected with viruses whose existence is mediated by, or depends upon,the enzyme reverse transcriptase. Conditions which may be prevented ortreated with the compounds of the present invention, especiallyconditions associated with HIV and other pathogenic retroviruses,include AIDS, AIDS-related complex (ARC), progressive generalizedlymphadenopathy (PGL), as well as chronic Central Nervous Systemdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines against above-mentioned conditions. Saiduse as a medicine or method of treatment comprises the administration toHIV-infected subjects of an amount effective to combat the conditionsassociated with HIV and other pathogenic retroviruses, especially HIV-1.In particular, the compounds of formula (I) may be used in themanufacture of a medicament for the treatment or the prevention of HIVinfections.

In view of the utility of the compounds of formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from viral infections, especially HIV infections. Saidmethod comprises the administration, preferably oral administration, ofan effective amount of a compound of formula (I), a N-oxide form, apharmaceutically acceptable addition salt, a quaternary amine or apossible stereoisomeric form thereof, to warm-blooded animals, includinghumans.

The present invention also provides compositions for treating viralinfections comprising a therapeutically effective amount of a compoundof formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

The compounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

To aid solubility of the compounds of formula (I), suitable ingredients,e.g. cyclodextrins, may be included in the compositions. Appropriatecyclodextrins are α-, β-, γ-cyclo-dextrins or ethers and mixed ethersthereof wherein one or more of the hydroxy groups of the anhydroglucoseunits of the cyclodextrin are substituted with C₁₋₆alkyl, particularlymethyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxy-methyl orcarboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxypropyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration compriseparticles consisting of a solid dispersion comprising a compound offormula (I) and one or more appropriate pharmaceutically acceptablewater-soluble polymers.

The term “a solid dispersion” used hereinafter defines a system in asolid state (as opposed to a liquid or gaseous state) comprising atleast two components, in casu the compound of formula (I) and thewater-soluble polymer, wherein one component is dispersed more or lessevenly throughout the other component or components (in case additionalpharmaceutically acceptable formulating agents, generally known in theart, are included, such as plasticizers, preservatives and the like).When said dispersion of the components is such that the system ischemically and physically uniform or homogenous throughout or consistsof one phase as defined in thermo-dynamics, such a solid dispersion willbe called “a solid solution”. Solid solutions are preferred physicalsystems because the components therein are usually readily bioavailableto the organisms to which they are administered. This advantage canprobably be explained by the ease with which said solid solutions canform liquid solutions when contacted with a liquid medium such as thegastro-intestinal juices. The ease of dissolution may be attributed atleast in part to the fact that the energy required for dissolution ofthe components from a solid solution is less than that required for thedissolution of components from a crystalline or microcrystalline solidphase.

The term “a solid dispersion” also comprises dispersions, which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates to asystem having domains or small regions wherein amorphous,microcrystalline or crystalline compound of formula (I), or amorphous,microcrystalline or crystalline water-soluble polymer, or both, aredispersed more or less evenly in another phase comprising water-solublepolymer, or compound of formula (I), or a solid solution comprisingcompound of formula (I) and water-soluble polymer. Said domains areregions within the solid dispersion distinctively marked by somephysical feature, small in size, and evenly and randomly distributedthroughout the solid dispersion.

Various techniques exist for preparing solid dispersions includingmelt-extrusion, spray-drying and solution-evaporation.

The solution-evaporation process comprises the following steps:

-   a) dissolving the compound of formula (I) and the water-soluble    polymer in an appropriate solvent, optionally at elevated    temperatures;-   b) heating the solution resulting under point a), optionally under    vacuum, until the solvent is evaporated. The solution may also be    poured onto a large surface so as to form a thin film, and    evaporating the solvent therefrom.

In the spray-drying technique, the two components are also dissolved inan appropriate solvent and the resulting solution is then sprayedthrough the nozzle of a spray dryer followed by evaporating the solventfrom the resulting droplets at elevated temperatures.

The preferred technique for preparing solid dispersions is themelt-extrusion process comprising the following steps:

-   a) mixing a compound of formula (I) and an appropriate water-soluble    polymer,-   b) optionally blending additives with the thus obtained mixture,-   c) heating and compounding the thus obtained blend until one obtains    a homogenous melt,-   d) forcing the thus obtained melt through one or more nozzles; and-   e) cooling the melt until it solidifies.

The terms “melt” and “melting” should be interpreted broadly. Theseterms not only mean the alteration from a solid state to a liquid state,but can also refer to a transition to a glassy state or a rubbery state,and in which it is possible for one component of the mixture to getembedded more or less homogeneously into the other. In particular cases,one component will melt and the other component(s) will dissolve in themelt thus forming a solution, which upon cooling may form a solidsolution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, theobtained products can be optionally milled and sieved.

The solid dispersion product may be milled or ground to particles havinga particle size of less than 600 μm, preferably less than 400 μm andmost preferably less than 125 μm.

The particles prepared as described hereinabove can then be formulatedby conventional techniques into pharmaceutical dosage forms such astablets and capsules.

It will be appreciated that a person of skill in the art will be able tooptimize the parameters of the solid dispersion preparation techniquesdescribed above, such as the most appropriate solvent, the workingtemperature, the kind of apparatus being used, the rate of spray-drying,the throughput rate in the melt-extruder

The water-soluble polymers in the particles are polymers that have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa.s more preferably of 1 to 700 mPa.s, and mostpreferred of 1 to 100 mPa.s. For example, suitable water-solublepolymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-,oligo- and polysaccharides such as trehalose, alginic acid or alkalimetal and ammonium salts thereof, carrageenans, galactomannans,tragacanth, agar-agar, gum arabic, guar gum and xanthan gum, polyacrylicacids and the salts thereof, polymethacrylic acids and the saltsthereof, methacrylate copolymers, polyvinylalcohol,polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate, combinations of polyvinylalcohol and polyvinylpyrrolidone,polyalkylene oxides and copolymers of ethylene oxide and propyleneoxide. Preferred water-soluble polymers are hydroxypropylmethylcelluloses.

Also one or more cyclodextrins can be used as water-soluble polymer inthe preparation of the above-mentioned particles as is disclosed in WO97/18839. Said cyclodextrins include the pharmaceutically acceptableunsubstituted and substituted cyclodextrins known in the art, moreparticularly α, β or γ cyclodextrins or the pharmaceutically acceptablederivatives thereof.

Substituted cyclodextrins, which can be used to prepare the particlesdescribed above include polyethers described in U.S. Pat. No. 3,459,731.Further substituted cyclodextrins are ethers wherein the hydrogen of oneor more cyclodextrin hydroxy groups is replaced by C₁₋₆alkyl,hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl or C₁₋₆alkyloxycarbonyl-C₁₋₆alkyl ormixed ethers thereof. In particular such substituted cyclodextrins areethers wherein the hydrogen of one or more cyclodextrin hydroxy groupsis replaced by C₁₋₃alkyl, hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or morein particular by methyl, ethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, carboxy-methyl or carboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-β-cyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

Another type of substituted cyclodextrins is sulfobutylcyclodextrines.

The ratio of the compound of formula (I) over the water soluble polymermay vary widely. For example ratios of 1/100 to 100/1 may be applied.Interesting ratios of the compound of formula (I) over cyclodextrinrange from about 1/10 to 10/1. More interesting ratios range from about1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I)in the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of thecompound of formula (I) but do not chemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

Yet another interesting way of formulating the compounds of formula (I)involves a pharmaceutical composition whereby the compounds of formula(I) are incorporated in hydrophilic polymers and applying this mixtureas a coat film over many small beads, thus yielding a composition whichcan conveniently be manufactured and which is suitable for preparingpharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating filmof a hydrophilic polymer and a compound of formula (I) and optionally aseal-coating layer.

Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the individual may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated subject and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned hereinabove are therefore only guidelines andare not intended to limit the scope or use of the invention to anyextent.

The present compounds of formula (I) can be used alone or in combinationwith other therapeutic agents, such as anti-virals, antibiotics,immunomodulators or vaccines for the treatment of viral infections. Theymay also be used alone or in combination with other prophylactic agentsfor the prevention of viral infections. The present compounds may beused in vaccines and methods for protecting individuals against viralinfections over an extended period of time. The compounds may beemployed in such vaccines either alone or together with other compoundsof this invention or together with other anti-viral agents in a mannerconsistent with the conventional utilization of reverse transcriptaseinhibitors in vaccines. Thus, the present compounds may be combined withpharmaceutically acceptable adjuvants conventionally employed invaccines and administered in prophylactically effective amounts toprotect individuals over an extended period of time against HIVinfection.

Also, the combination of one or more additional antiretroviral compoundsand a compound of formula (I) can be used as a medicine. Thus, thepresent invention also relates to a product containing (a) a compound offormula (I), and (b) one or more additional antiretroviral compounds, asa combined preparation for simultaneous, separate or sequential use inanti-HIV treatment. The different drugs may be combined in a singlepreparation together with pharmaceutically acceptable carriers. Saidother antiretroviral compounds may be any known antiretroviral compoundssuch as suramine, pentamidine, thymopentin, castanospermine, dextran(dextran sulfate), foscarnet-sodium (trisodium phosphono formate);nucleoside reverse transcriptase inhibitors (NRTIs), e.g. zidovudine(AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine(d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC (Reverset™),alovudine (MIV-310), amdoxovir (DAPD), elvucitabine (ACH-126,443), andthe like; non-nucleoside reverse transcriptase inhibitors (NNRTIs) suchas delarvidine (DLV), efavirenz (EFV), nevirapine (NVP), capravirine(CPV), calanolide A, TMC120, etravirine (TMC125), TMC278, BMS-561390,DPC-083 and the like; nucleotide reverse transcriptase inhibitors(NtRTIs), e.g. tenofovir (TDF) and tenofovir disoproxil fumarate, andthe like; compounds of the TIBO(tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]-benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and the like;inhibitors of trans-activating proteins, such as TAT-inhibitors, e.g.RO-5-3335; REV inhibitors; protease inhibitors e.g. ritonavir (RTV),saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV),amprenavir (VX-478), TMC-126, BMS-232632, VX-175, DMP-323, DMP-450(Mozenavir), nelfinavir (AG-1343), atazanavir (BMS 232,632), palinavir,TMC-114, R0033-4649, fosamprenavir (GW433908 or VX-175), P-1946, BMS186,318, SC-55389a, L-756,423, tipranavir (PNU-140690), BILA 1096 BS,U-140690, and the like; entry inhibitors which comprise fusioninhibitors (e.g. T-20, T-1249), attachment inhibitors and co-receptorinhibitors; the latter comprise the CCR5 antagonists and CXR4antagonists (e.g. AMD-3100); examples of entry inhibitors areenfuvirtide (ENF), GSK-873,140, PRO-542, SCH-417,690, TNX-355, maraviroc(UK-427,857); a maturation inhibitor for example is PA-457 (PanacosPharmaceuticals); inhibitors of the viral integrase; ribonucleotidereductase inhibitors (cellular inhibitors), e.g. hydroxyurea and thelike.

By administering the compounds of the present invention with otheranti-viral agents which target different events in the viral life cycle,the therapeutic effect of these compounds can be potentiated.Combination therapies as described above exert a synergistic effect ininhibiting HIV replication because each component of the combinationacts on a different site of HIV replication. The use of suchcombinations may reduce the dosage of a given conventionalanti-retroviral agent which would be required for a desired therapeuticor prophylactic effect as compared to when that agent is administered asa monotherapy. These combinations may reduce or eliminate the sideeffects of conventional single anti-retroviral therapy while notinterfering with the anti-viral activity of the agents. Thesecombinations reduce potential of resistance to single agent therapies,while minimizing any associated toxicity. These combinations may alsoincrease the efficacy of the conventional agent without increasing theassociated toxicity.

The compounds of the present invention may also be administered incombination with immunomodulating agents, e.g. levamisole, bropirimine,anti-human alpha interferon antibody, interferon alpha, interleukin 2,methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor,naltrexone and the like; antibiotics, e.g. pentamidine isethiorate andthe like; cholinergic agents, e.g. tacrine, rivastigmine, donepezil,galantamine and the like; NMDA channel blockers, e.g. memantine toprevent or combat infection and diseases or symptoms of diseasesassociated with HIV infections, such as AIDS and ARC, e.g. dementia. Acompound of formula (I) can also be combined with another compound offormula (I).

Although the present invention focuses on the use of the presentcompounds for preventing or treating HIV infections, the presentcompounds may also be used as inhibitory agents for other viruses whichdepend on similar reverse transcriptases for obligatory events in theirlife cycle.

The present invention is explained in greater detail in the followingnon-limiting examples.

EXAMPLES Example 1 Synthesis of Intermediates B, C and D

Preparation of Intermediate B

A mixture of A (0.420 mol) in 2-methoxyethylether (diglyme, 250 ml) wasstirred at 100° C. for 30 minutes. Then a mixture of cyanamide (0.630mol) in water (30 ml) was added portion wise during 45 minutes. Afterstirring 24 h at 100° C., cyanamide (0.210 mol) was added. The mixturewas stirred again at 100° C. for 48 h. The mixture was evaporated untildryness and the residue was crystallized from acetone. Yield: 70.5 g ofintermediate B (85%, melting point: 225° C.).

Preparation of Intermediate C

A mixture of B (0.356 mol) and 2-acetylbutyrolactone (1.068 mol) inethanol (200 ml) and trietylamine (75 ml) was stirred at reflux for 48h. The mixture was cooled and the precipitate was filtrated, then washedwith ethanol and dried. Yield: 71 g of C (74%, melting point>250° C.).

Preparation of Intermediate D

A mixture of C (0.189 mol) and phosphorus oxychloride (200 ml) wasstirred at 60° C. for 1 week. After cooling phosphorus oxychloride wasevaporated. Water and K₂CO₃ 10% was added and the mixture was extractedwith CH₂Cl₂. The organic layer was dried over magnesium sulfate,filtered and the solvent evaporated. Yield: 45 g of D (78%, meltingpoint: 168° C.).

Example 2 Preparation of Intermediate E9(4-bromo-2-chloro-6-fluoroaniline)

N-chlorosuccinimide (0.199 mol) was added portionwise to a mixture of4-bromo-2-fluoroaniline (0.158 mol) in acetonitrile (50 ml). The mixturewas stirred at reflux for 2 hours, cooled and poured in a mixture ofwater and K₂CO₃ 10%. The mixture was extracted with CH₂Cl₂. The organiclayer was dried over magnesium sulfate, filtered and the solventevaporated. The residue was purified by column chromatography oversilica gel (eluent: cyclohexane/ethyl acetate 80/20; 35-70 μm). The purefractions were collected and the solvent evaporated. Yield: 31.6 g of4-bromo-2-chloro-6-fluoroaniline, intermediate E9 (89%, melting point:<50° C.). Intermediate E9 was used to prepare intermediate F9 (see Table1).

Example 3 Preparation of Intermediates F3, F4, F6

A mixture of 4-bromo-2-methylaniline (0.0268 mol), intermediate E3,palladium (0) acetate (0.00537 mol), tri-o-tolylphosphine (0.0268 mol)and acrylonitrile (0.0896 mol) in triethylamine (0.107 mol) andacetonitrile (70 ml) was stirred at 140° C. in a stainless-steel bombfor 18 h. After cooling, the mixture was filtered over celite and thefiltrate was poured in water and extracted with CH₂Cl₂. The organiclayer was dried over magnesium sulfate, filtered and the solventevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/Cyclohexane 50/50; 35-70 μm). The purefractions were collected and the solvent evaporated. Yield: 3.2 g ofintermediate F3 (75%, melting point: 105° C.)

Preparation of Intermediates F4 and F6

Intermediate F4 was prepared as described above for the preparation F3,using 4-bromo-2-ethylaniline as starting material. In a second step,N-bromosuccinimide (0.015 mol) was added portionwise to a mixture of4-acrylonitrile-2-ethylaniline F4 (0.012 mol) in acetonitrile (25 ml).The mixture was stirred at room temperature overnight then poured in amixture of water and K₂CO₃ 10%. The mixture was extracted with CH₂Cl₂.The organic layer was dried over magnesium sulfate, filtered and thesolvent evaporated. The residue was purified by column chromatographyover silica gel (eluent: Cyclohexane/ethyl acetate 90/10; 15-40 μm). Thepure fractions were collected and the solvent evaporated. Yield: 0.75 gof intermediate F6 (26%).

Example 4 Preparation of Intermediates H, I and J

Preparation of Intermediate H

A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0516 mol) and4-(2-cyanoethenyl)-2,6-dimethylphenylamine (0.0516 mol) was stirred at140° C. in an oil bath for 45 minutes, then poured in a mixture of waterand K₂CO₃ 10%. The precipitate was filtered and the filtrate extractedwith CH₂Cl₂. The organic layer was dried over magnesium sulfate,filtered and the solvent evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂100; 35-70 μm). The purefractions were collected and the solvent evaporated, yielding 6.0 g ofintermediate H (35%, melting point: >250° C.).

Preparation of Intermediate I

A mixture of intermediate H (0.0182 mol) and 4-cyanoaniline (0.0182 mol)was heated at fusion for 5 minutes, then poured in a mixture of waterand K₂CO₃ 10%. CH₂Cl₂ and a small quantity of MeOH were added and theprecipitate was filtered and dried, yielding 7.4 g of intermediate I(95%, melting point: >250° C.)

Preparation of Intermediate J

A mixture of intermediate I (0.0180 mol) and tin (II) chloride dihydrate(0.125 mol) in ethanol (100 ml) was stirred at 70° C. overnight, thenpoured in a mixture of water and K₂CO₃ 10%. The precipitate was filteredover celite. The filtrate was removed and the precipitate was washedwith CH₂Cl₂ and THF. The solvent was evaporated. Yield: 6.0 g ofintermediate J (87%, melting point: >250° C.).

Example 5 Preparation of Intermediates K, L and M(6-chloro-2-fluorophenyl Analogs of Intermediates H, I and J)

A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0153 mol) and4-(2-cyanoethenyl)-6-chloro-2-fluoro-phenylamine (0.0153 mol) was heatedat fusion for 5 minutes, then poured in a mixture of water and K₂CO₃ 10%and extracted with CH₂Cl₂. The organic layer was dried over magnesiumsulfate, filtered and the solvent evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂ 100; 35-70 μm).

The pure fractions were collected and the solvent evaporated. Yield: 1.9g of2-chloro-4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-nitro-pyrimidine,intermediate K (35%, melting point: 217° C.).

A mixture of intermediate K (0.000424 mol) and 4-cyanoaniline (0.000424mol) was heated at fusion for 5 minutes, then poured in a mixture ofwater and K₂CO₃ 10%. CH₂Cl₂ and a small quantity of MeOH was added andthe precipitate was filtered and dried, yield: 1.34 g of4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-nitro-pyrimidine]amino]benzonitrile,intermediate L (73%, melting point: >250° C.)

A mixture of intermediate L (0.00306 mol) and tin (II) chloridedihydrate (0.0214 mol) in ethanol (20 ml) was stirred at 70° C.overnight, then poured in a mixture of water and K₂CO₃ 10%. Theprecipitate was filtered over celite. The filtrate was removed and theprecipitate was washed with CH₂Cl₂ and THF. The solvent was evaporated.Yield: 1.1 g of4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino1-5-amino-pyrimidine]amino]benzonitrile,intermediate M (89%, melting point: >250° C.).

Example 6 Preparation of Dihydro-Pyrrolopyrimidine Compound 1

A mixture of F3 (0.00126 mol) and D (0.00126 mol) was stirred at 180° C.in an oil bath for 20 hours, then poured in a mixture of water and K₂CO₃10% and extracted with CH₂Cl₂. The organic layer was dried overmagnesium sulfate, filtered and the solvent evaporated. The residue waspurified by column chromatography over silica gel (eluent:MeOH/AcNH₄/THF 40/40/20; Kromasil C18, 10 μm). The pure fractions werecollected and the solvent evaporated. Yield: 0.18 g of compound 1 (E/Z:95/5) and 0.124 g of compound 1 (E/Z: 65/35) (overall yield 61%, meltingpoint (E/Z: 95/5): 244° C.).

Example 7 Preparation of Dihydro-Pyrrolopyrimidine Derivative 14

To a nitrogen flushed solution of 1(0.00051 mol) in MeOH (20 ml),palladium on activated carbon 10% Pd (0.2 g, 10% wt) was added. Themixture was stirred at room temperature under 3 bars of hydrogen for 20hours, then filtered over celite and the solvent was evaporated. Theresidue was crystallized from CH₂Cl₂/diisopropyl-ethylether. Yield: 0.05g of compound 14 (25%, melting point: 195° C.).

Example 8 Preparation of Pyrrolopyrimidine Derivative 28

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.00222 mol) was added to amixture of compound 11 (0.000738 mol), prepared following similarprocedures as in example 1, in 1,4-dioxane (10 ml). The mixture wasstirred at reflux for 2 hours, then cooled and poured on ice. Theprecipitate was filtered and purified by column chromatography oversilica gel (eluent: CH₂Cl₂/MeOH/NH₄OH 98/2/0.1; 10 μm). The purefractions were collected and the solvent evaporated. The residue wascrystallized from diisopropyl-ethylether. Yield: 0.022 g of compound 28(7%, melting point: 217° C.).

Example 9 Preparation of Pyrrolopyrimidine Derivative 34

Preparation of Dihydro-Pyrrolopyrimidine Compound 33

A mixture of ethyl 4-amino-3,5-dimethylbenzoate G (0.0155 mol) and D(0.0155 mol) was stirred at 180° C. in an oil bath for 20 hours, thenpoured in a mixture of water and K₂CO₃ 10% and extracted with CH₂Cl₂.The organic layer was dried over magnesium sulfate, filtered and thesolvent evaporated. The residue was purified by column chromatographyover silica gel (eluent: CH₂Cl₂; 70-200 μm). The pure fractions werecollected and the solvent evaporated. Yield: 2.2 g of compound 33 (33%,melting point: 92° C.).

Preparation of Dihydro-Pyrrolopyrimidine Derivative 33a

Compound 33 (0.00234 mol) was added portion wise to a mixture of lithiumaluminum hydride (0.00702 mol) in THF (15 ml) at 0° C. The mixture wasstirred at room temperature for 3 hours. Ethyl acetate was added, thenwater and the mixture was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, filtered and the solvent wasevaporated. The residue was engaged in the next step with no furtherpurification.

Preparation of Dihydro-Pyrrolopyrimidine Derivative 33b

To the residue of compound 33a (0.860 g) in CH₂Cl₂ was added manganese(IV) oxide (0.0104 mol) and the mixture was stirred at room temperaturefor 20 hours. After filtration over celite, the solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂; 70-200 μm). The pure fractions were collected and thesolvent evaporated. Yield: 0.160 g of compound 33b (18% for the twosteps, melting point: oil).

Preparation of Dihydro-Pyrrolopyrimidine Compound 34

To a mixture of diethyl-(1-cyanoethyl)-phosphonate (0.000782 mol) in THF(5 ml) was added at 0° C. under nitrogen potassium tert-butoxide(0.000782 mol) and the mixture was stirred at room temperature for 1hour. Compound 33b (0.000261 mol) was added and the mixture was stirredat room temperature for 20 hours, then poured in water and extractedwith CH₂Cl₂. The organic layer was dried over magnesium sulfate,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂; 35-70 μm). Thepure fractions were collected and the solvent evaporated. The residuewas crystallized from diisopropyl-ethylether. Yield: 0.075 g of compound34 (E/Z: 50/50) (68%, melting point: 105° C.).

Example 10 Preparation of Compound 20

A mixture of J (0.000524 mol) and triethyl orthoformate (5 ml) wasstirred at 100° C. for 20 hours. After cooling, water and K₂CO₃ 10% wasadded. The precipitate was filtered off and dried. Yield: 0.155 g ofcompound 20 (76%, melting point>250° C.).

Example 11 Preparation of Compound 21

A mixture of J (0.000524 mol) and 2-furaldehyde (0.00524 mol) innitrobenzene (5 ml) was stirred at 180° C. for 20 hours. After cooling,the residue was filtered over silica gel to eliminate nitrobenzene. Thesolvent was evaporated and the residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/MeOH/NH₄OH 99/1/0.1; 10μm). The pure fractions were collected and the solvent evaporated. Theresidue was crystallized from diisopropyl-ethylether. Yield: 0.055 g ofcompound 21 (23%, melting point: 236° C.).

Example 12 Preparation of Compound 29 (Triazolo Derivative)

Sodium nitrite (0.000629 mol) in water (2 ml) was slowly added at 0° C.to a mixture of J (0.000524 mol) in water (2.5 ml) and acetic acid (1.5ml). The mixture was stirred at room temperature for 5 hours. Theprecipitate was filtered, washed with water and diisopropyl-ethyletherand dried. Yield: 0.110 g of compound 29 (53%, melting point >250° C.).

Example 13 Preparation of Compound 30

The same procedure as in example 12 was used for the preparation of thisderivative starting with 0.000370 mol of J analog and 0.000444 mol ofsodium nitrite. Yield: 0.065 g of compound 30 (42%, melting point>250°C.).

Example 14 Preparation of Compound 31

Thiophosgene (0.000786 mol) was slowly added dropwise at 0° C. to amixture of J (0.000524 mol) in 1,4-dioxane (5 ml). The mixture wasstirred at room temperature for 4 hours and thiophosgene was added(0.000393 mol) and the mixture was stirred overnight. NH₄OH was slowlyadded at 0° C. and the mixture was extracted with CH₂Cl₂. The organiclayer was dried over magnesium sulfate, filtered and the solventevaporated. Yield: 0.105 g of compound 31 (47%, melting point>250° C.)

Example 15 Preparation of Compound 32

The same procedure as in example 14 was used for the preparation ofcompound 32, starting with 0.000370 mol of intermediate M and 0.000554mol of thiophosgene. Yield: 0.140 g of compound 32 (85%, meltingpoint>250° C.).

Example 16 Preparation of Compound 26

Cyanogen bromide (0.000793 mol) was added portion wise at roomtemperature to intermediate J (0.000524 mol) in EtOH (6 ml) and THF (5ml). The mixture was stirred at room temperature overnight. Cyanogenbromide (0.000264 mol) was added and the mixture was stirred at roomtemperature one day. The mixture was poured in a mixture of water andK₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer was dried overmagnesium sulfate, filtered and the solvent evaporated. The residue wascrystallized from CH₂Cl₂. Yield: 0.092 g of 26 (43%, meltingpoint: >250° C.).

Tables 1-6 list intermediates and compounds that were prepared accordingto one of the above Examples (Ex. No.).

TABLE 1

Comp. Nr. Ex. No. R¹ R² Phys. Data F1 3 F F 168° C. F2 3 Et Et  69° C.F3 3 Me H 105° C. F4 3 Et H Oil F5 3 F H  99° C. F6 3 Et Br  75° C. F7 3Me Br  87° C. F8 3 Cl Cl 131° C. F9 2 + 3 F Cl 144° C. F10 3 OMe Me 110°C.

TABLE 2

Phys. Data and Comp. Nr. Ex. No. R⁴ R^(4a) stereochemistry 1 6 Me H(E/Z: 95/5); 244° C. 2 6 F F (E/Z: 95/5); >250° C. 3 6 Et Et (E/Z:95/5); 139° C. 4 6 Et H (E); 210° C. 5 6 F H (E/Z: 94/6): >250° C. 6 6Et Br (E/Z: 98/2); 146° C.  7a 6 Cl Cl (E/Z: 97:3); 151° C.  7b 6 Cl Cl(E/Z: 88/12) 8 6 OMe Me (E); >250° C. 9 6 Me Br (E/Z: 85/15); 130° C.10  6 F Cl (E); 138° C. 11  6 Me Me (E/Z: 83/17); 215° C. 12  6 F F(Z); >250° C. 13  6 F Cl (Z); >250° C.

TABLE 3

Comp. Nr. Ex. No. R⁴ R^(4a) Phys. Data 14 7 Me H 195° C. 15 7 Me Me 195°C. 16 7 Et Et 68-70° C. 17 7 Et H 176° C. 18 7 F H 189° C. 19 7 F F 191°C.

TABLE 4

Comp. Phys. Data and stereo- No. Ex. No. R⁴ R^(4a) R⁵ chemistry 20 10 MeMe H (E); >250° C. 21 11 Me Me

(E); 236° C. 22 11 Me Me ethyl (E); >250° C. 23 11 Me Me

(E); >250° C. 24 11 F Cl H (E/Z: 93/7); >250° C. 25 11 Me Me

(E); 231° C. 26 16 Me Me NH₂ (E); >250° C. 27 16 F Cl NH₂ (E); >250° C.

TABLE 5

Ex. Phys. Data and Comp. Nr. No. A—B R⁴ R^(4a) Q stereochemistry 28  8—CH═CH— Me Me Me 217° C. 29 12 —N═N— Me Me H (E); >250° C. 30 13 —N═N— FCl H (E); >250° C. 31 14 —C(═S)—NH— Me Me H (E/Z): 98/2; >250° C. 32 15—C(═S)—NH— F Cl H (E/Z): 93/7; >250° C.

TABLE 6

Comp. Ex. Phys. Data and Nr. No. R³ stereochemistry 33 9 —COOEt 92° C.34 9 —CH═C(CH₃)CN (E/Z): 50/50; 105° C.Formulation ExamplesCapsules

A compound of formula (I) is dissolved in organic solvent such asethanol, methanol or methylene chloride, preferably, a mixture ofethanol and methylene chloride. Polymers such as polyvinylpyrrolidonecopolymer with vinyl acetate (PVP-VA) or hydroxypropyl-methylcellulose(HPMC), typically 5 mPa·s, are dissolved in organic solvents such asethanol, methanol methylene chloride. Suitably the polymer is dissolvedin ethanol. The polymer and compound solutions are mixed andsubsequently spray dried. The ratio of to compound/polymer is selectedfrom 1/1 to 1/6. Intermediate ranges can be 1/1.5 and 1/3. A suitableratio can be 1/6. The spray-dried powder, a solid dispersion, issubsequently filled in capsules for administration. The drug load in onecapsule ranges between 50 and 100 mg depending on the capsule size used.

Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere is added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10,000 tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methylcellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethylcellulose in 150 ml ofdichloromethane. Then there is added 75 ml of dichloromethane and 2.5 ml1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolvedin 75 ml of dichloromethane. The latter solution is added to the formerand then there is added 2.5 g of magnesium octadecanoate, 5 g ofpolyvinylpyrrolidone and 30 ml of concentrated color suspension and thewhole is homogenized. The tablet cores are coated with the thus obtainedmixture in a coating apparatus.

Antiviral Spectrum:

Because of the increasing emergence of drug resistant HIV strains, thepresent compounds were tested for their potency against clinicallyisolated HIV strains harboring several mutations. These mutations areassociated with resistance to reverse transcriptase inhibitors andresult in viruses that show various degrees of phenotypiccross-resistance to the currently commercially available drugs such asfor instance AZT and delavirdine.

The antiviral activity of the compound of the present invention has beenevaluated in the presence of wild type HIV and HIV mutants bearingmutations at the reverse transcriptase gene. The activity of thecompounds is evaluated using a cellular assay and the residual activityis expressed in pEC₅₀ values. The columns IIIB and A-G in the table listthe pEC₅₀ values against various strains IIIB, A-G.

-   Strain IIIB is wild type HIV-LAI strain-   Strain A contains mutation Y181C in HIV reverse transcriptase,-   Strain B contains mutation K103N in HIV reverse transcriptase,-   Strain C contains mutation L100I in HIV reverse transcriptase,-   Strain D contains mutation Y188L in HIV reverse transcriptase,-   Strain E contains mutations L100I and K103N in HIV reverse    transcriptase,-   Strain F contains mutations K103N and Y181C in HIV reverse    transcriptase, and-   Strain G contains mutations L100I, K103N, Y181C, V179I E138G L214F,    V278V/I-   and A327A/V in HIV reverse transcriptase.

Comp. number IIIB A B C D E F G  1 8.4 7.9 9 8.9 7.7 7.8 7.1 5.5  2 9.17.9 9.2 9.3 8.4 9.1 7.4 5.7  3 7.9 7.8 8.5 8.7 7.8 8.5 7.7 5.7  4 8.48.3 9 9 7.9 8.1 7.6 5.1  5 7.7 6.3 7.9 7.8 6.6 6.9 — <4.6  6 8.3 7.7 8.38.4 7.5 8.3 7.5 5.5  7a 8.7 7.9 8.7 9.1 7.7 8.6 7.7 5.4  7b 9.1 8.1 99.1 7.7 8.5 7.7 5.4  8 8.5 7.6 8.4 8.3 7.5 7.6 7.2 4.9  9 8.9 8.3 8.48.7 8.4 7.8 7.7 <4.6 10 9.2 8.4 9.1 9.2 8 8.7 7.9 5.7 11 8.8 8.2 9 8.88.1 8.4 7.9 5.4 13 8.4 7.1 8.4 8.4 7 7.8 7 5.1 14 8.9 7.8 8.5 8.4 7 7.26.9 5.5 15 9 8.2 8.6 — 7.3 8 8 5.7 16 8.2 7.7 8.2 8.6 7 8.1 7.3 5.8 17 98.2 8.9 8.6 7.7 7.8 7.2 5.7 20 9.7 8.6 9.2 9.2 7.8 8.1 7.4 5.7 22 8.46.5 8.4 6.5 5.8 5.5 5.8 — 23 7.7 7.1 7.6 7.5 7.7 6.3 6.4 5.7 24 10 8.510 9.7 7.9 8.2 7.9 5.7 25 8.1 7.5 7.6 7.2 7.5 5.9 7.2 5.6 26 8.6 7.6 7.97.7 7.1 6.9 7.2 4.9 27 7.7 7.1 — 7.1 6.3 6.2 6.7 5.2 28 8.5 7.9 8.5 8.67.7 8.5 7.8 5.7 29 9.1 7.8 8.8 8.3 7.7 7.1 — 5.4 31 9 7.9 8.6 8.6 7.16.4 7.4 4.8 33 7.3 5.6 6.9 6.1 6.2 5.4 5.5 4.9 34 8.7 7.8 8.6 8.4 7.77.8 7.7 5.4

The invention claimed is:
 1. A compound of formula

a N-oxide; a pharmaceutically acceptable addition salt; a quaternaryamine; or a stereochemically isomeric form thereof, wherein-a¹=a²-a³=a⁴- represents a bivalent radical of a formula selected fromthe group consisting of:—CH═CH—CH═CH—  (a-1);—N═CH—CH═CH—  (a-2);—N═CH—N═CH—  (a-3);—N═CH—CH═N—  (a-4); and—N═N—CH═CH—  (a-5); -b¹=b²-b³=b⁴- represents a bivalent radical of aformula selected from the group consisting of:—CH═CH—CH═CH—  (b-1);—N═CH—CH═CH—  (b-2);—N═CH—N═CH—  (b-3);—N═CH—CH═N—  (b-4); and—N═N—CH═CH—  (b-5); n is 0, 1, 2, 3 and in case -a¹=a²-a³=a⁴- is (a-1),then n may also be 4; m is 0, 1, 2, 3 and in case -b¹=b²-b³=b⁴- is(b-1), then m may also be 4; -A-B— represents a bivalent radical of aformula:—CH₂—CH₂—  (c-3); or—CH═CH—  (c-6); R¹ is a member selected from the group consisting of:hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; and C₁₋₆alkyl substituted with a member selectedfrom the group consisting of: formyl, C₁₋₆alkylcarbonyl, andC₁₋₆alkyloxycarbonyl; each R² independently is selected from the groupconsisting of: hydroxy; halo; C₁₋₆alkyl optionally substituted with one,two or three substituents each independently selected from halo, cyanoand —C(═O)R⁶; C₃₋₇cycloalkyl; C₂₋₆alkenyl optionally substituted withone, two or three substituents each independently selected from halo,cyano and —C(═O)R⁶; C₂₋₆alkynyl optionally substituted with one, two orthree substituents each independently selected from halo, cyano and—C(═O)R⁶; C₁₋₆alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- ordi(C₁₋₆alkyl)amino; polyhalomethyl; polyhalomethylthio; —S(═O)_(p)R⁶;—NH—S(═O)_(p)R⁶; —C(═O)R⁶;—NHC(═O)H; —C(═O)NHNH₂; NHC(═O)R⁶; andC(═NH)R⁶; R^(2a) is a member selected from the group consisting of:cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy wherein theC₁₋₆alkyl moiety of the C₁₋₆alkyloxy may optionally be substituted withcyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; C(═O)—R¹⁵;—CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one, two or threesubstituents each independently selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyl substituted withhydroxy and a second substituent selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionallysubstituted with one, two or three substituents each independentlyselected from halo, cyano, NR⁹R¹⁰; —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl andR⁷; C₂₋₆alkenyl substituted with one, two or three substituents eachindependently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,—C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl substituted with one, two or threesubstituents each independently selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷; and—X—R⁷; R³ is a member selected from the group consisting of: cyano;aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy wherein theC₁₋₆alkyl moiety of the C₁₋₆alkyloxy may optionally be substituted withcyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;—CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one, two or threesubstituents each independently selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyl substituted withhydroxy and a second substituent selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionallysubstituted with one, two or three substituents each independentlyselected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl andR⁷; C₂₋₆alkenyl substituted with one, two or three substituents eachindependently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,—C(═O)—C₁₋₆alkyl and R⁷; C₂₋₆alkynyl substituted with one, two or threesubstituents each independently selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl and R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷; and—X—R⁷; X is a member selected from the group consisting of: —NR¹—, —O—,—C(═O)—, —S—, and —S(═O)_(p)—; each R⁴ independently is a memberselected from the group consisting of: halo; hydroxy; C₁₋₆alkyloptionally substituted with one, two or three substituents eachindependently selected from halo, cyano and —C(═O)R⁶; C₂₋₆alkenyloptionally substituted with one, two or three substituents eachindependently selected from halo, cyano and —C(═O)R⁶; C₂₋₆alkynyloptionally substituted with one, two or three substituents eachindependently selected from halo, cyano and —C(═O)R⁶; C₃₋₇cycloalkyl;C₁₋₆alkyloxy; cyano; nitro; polyhaloC₁₋₆alkyl; polyhaloC₁₋₆alkyloxy;aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl; formyl; amino; mono- ordi(C₁₋₄alkyl)amino; and R⁷; Q is a member selected from the groupconsisting of: hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, and—NR⁹R¹⁰; R⁶ is a member selected from the group consisting of:C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino, and polyhaloC₁₋₄alkyl; R⁷is a member selected from the group consisting of: a monocyclic,bicyclic or tricyclic saturated, partially saturated or aromaticcarbocycle; or a monocyclic, bicyclic or tricyclic saturated, partiallysaturated or aromatic heterocycle; wherein each of said carbocyclic orheterocyclic ring systems may optionally be substituted with one, two,three, four or five substituents each independently selected from thegroup consisting of: halo, hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono and di(C₁₋₆alkyl)aminoC₁₋₆ alkyl,formyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkyloxy, aminocarbonyl, —CH(═N—O—R⁸), R^(7a), —X—R^(7a) andR^(7a)—C₁₋₄alkyl; R^(7a) is a member selected from the group consistingof: a monocyclic, bicyclic or tricyclic saturated, partially saturatedor aromatic carbocycle; or a monocyclic, bicyclic or tricyclicsaturated, partially saturated or aromatic heterocycle; wherein each ofsaid carbocyclic or heterocyclic ring systems may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the group consisting of: halo, hydroxy,mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono ordi(C₁₋₆alkyl)amino C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, and—CH(═N—O—R⁸); R⁸ is a member selected from the group consisting of:hydrogen, C₁₋₄alkyl, aryl or arylC₁₋₄alkyl; R⁹ and R¹⁰ eachindependently are a member selected from the group consisting of:hydrogen; hydroxy; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; amino; mono- or di(C₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyl)aminocarbonyl; —CH(═NR¹¹) and R⁷ wherein each of theaforementioned C₁₋₆alkyl groups may optionally and each individually besubstituted with one or two substituents each independently selectedfrom the group consisting of: hydroxy, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino,imino, mono- or di(C₁₋₄alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, and R⁷; or R⁹ and R¹⁰ may be takentogether to form a bivalent or trivalent radical of a formula selectedfrom the group consisting of:—CH₂—CH₂—CH₂—CH₂—  (d-1);—CH₂—CH₂—CH₂—CH₂—CH₂—  (d-2);—CH₂—CH₂—O—CH₂—CH₂—  (d-3);—CH₂—CH₂—S—CH₂—CH₂—  (d-4);—CH₂—CH₂—NR¹²—CH₂—CH₂—  (d-5);—CH₂—CH═CH—CH₂—  (d-6); and═CH—CH═CH—CH═CH—  (d-7); R¹¹ is a member selected from the groupconsisting of: cyano; C₁₋₄alkyl optionally substituted withC₁₋₄alkyloxy, cyano, amino, mono- or di(C₁₋₄alkyl)amino oraminocarbonyl; C₁₋₄alkylcarbonyl; C₁₋₄alkyloxycarbonyl; aminocarbonyl;and mono- or di(C₁₋₄alkyl)aminocarbonyl; R¹² is hydrogen or C₁₋₄alkyl;R¹³ and R¹⁴ each independently are a member selected from the groupconsisting of: C₁₋₆alkyl optionally substituted with cyano oraminocarbonyl; C₂₋₆alkenyl optionally substituted with cyano oraminocarbonyl; and C₂₋₆alkynyl optionally substituted with cyano oraminocarbonyl; R¹⁵ is C₁₋₆alkyl substituted with cyano or aminocarbonyl;R¹⁶ is C₁₋₆alkyl optionally substituted with cyano, aminocarbonyl, orR⁷; each p is 1 or 2; each aryl is phenyl or phenyl substituted withone, two, three, four or five substituents each independently selectedfrom the group consisting of: halo, hydroxy, mercapto, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,aminocarbonyl, a radical Het and —X-Het; and Het is a member selectedfrom the group consisting of: pyridyl, thienyl, furanyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolylquinolinyl, benzothienyl, and benzofuranyl; wherein each of theaforementioned Het may optionally be substituted with one or twoC₁₋₄alkyl radicals.
 2. A compound according to claim 1, wherein-a¹=a²-a³=a⁴- represents a bivalent radical of formula—CH═CH—CH═CH—   (a-1); -b¹=b²-b³=b⁴- represents a bivalent radical offormula—CH═CH—CH═CH—   (b-1); n is 0, 1 or 2; m is 0, 1 or 2; and R¹ is amember selected from the group consisting of: hydrogen; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; and C₁₋₆alkyloxycarbonyl.
 3. A compoundaccording to claim 1, wherein the compound has the formula

wherein R¹, R², R^(2a), R³, R⁴, -A-B—, m, n and Q are as defined inclaim
 1. 4. A compound according to claim 1, wherein the compound hasthe formula

wherein R¹, R^(2a), R³, R⁴, -A-B— and Q are as defined in claim
 1. 5. Acompound according to claim 1, wherein R² is a member selected from thegroup consisting of: hydroxy; halo; C₁₋₆alkyl optionally substitutedwith one substituent selected from halo, cyano and —C(═O)R⁶; C₂₋₆alkenyloptionally substituted with one substituent selected from halo, cyano or—C(═O)R⁶; C₂₋₆alkynyl optionally substituted with one substituentselected from halo, cyano or —C(═O)R⁶; C₁₋₆alkyloxycarbonyl; carboxyl;cyano; nitro; amino; mono- or di(C₁₋₆alkyl)amino; and trifluoromethyl;R^(2a) is a member selected from the group consisting of: cyano;aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy wherein theC₁₋₆alkyl moiety of the C₁₋₆alkyloxy may optionally be substituted withcyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;—CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent selectedfrom halo, cyano, —C(═O)—NR⁹R¹⁰, and —C(═O)—C₁₋₆alkyl; C₁₋₆alkylsubstituted with hydroxy and a second substituent selected from halo,cyano, —C(═O)—NR⁹R¹⁰, and —C(═O)—C₁₋₆alkyl; C₁₋₆alkyloxyC₁₋₆alkyloptionally substituted with one substituent selected from halo, cyano,—C(═O)—NR⁹R¹⁰, and —C(═O)—C₁₋₆alkyl; C₂₋₆alkenyl substituted with onesubstituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰, and—C(═O)—C₁₋₆alkyl; and C₂₋₆alkynyl substituted with one substituentselected from halo, cyano, —C(═O)—NR⁹R¹⁰, and —C(═O)—C₁₋₆alkyl; R³ is amember selected from the group consisting of: cyano; aminocarbonyl;amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy wherein C₁₋₆alkyl may optionally besubstituted with cyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴;—C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with onesubstituent selected from halo, cyano, and —C(═O)—NR⁹R¹⁰; C₁₋₆alkylsubstituted with hydroxy and a second substituent selected from halo,cyano, and —C(═O)—NR⁹R¹⁰; C₁₋₆alkyloxyC₁₋₆alkyl optionally substitutedwith one substituent selected from halo, cyano, and —C(═O)—NR⁹R¹⁰;C₂₋₆alkenyl substituted with one substituent selected from halo, cyano,and —C(═O)—NR⁹R¹⁰; and C₂₋₆alkynyl substituted with one substituentselected from halo, cyano, and —C(═O)—NR⁹R¹⁰; and R⁴ is a memberselected from the group consisting of: halo; hydroxy; C₁₋₆alkyloptionally substituted with one substituent selected from halo, cyanoand —C(═O)R⁶; C₂₋₆alkenyl optionally substituted with one substituentselected from halo, cyano and —C(═O)R⁶; C₂₋₆alkynyl optionallysubstituted with one substituent selected from halo, cyano and —C(═O)R⁶;C₃₋₇cycloalkyl; C₁₋₆alkyloxy; cyano; nitro; polyhaloC₁₋₆alkyl;polyhaloC₁₋₆alkyloxy; aminocarbonyl; mono- ordi(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl;formyl; amino; mono- or di(C₁₋₄alkyl)amino and R⁷.
 6. A compoundaccording to claim 1, wherein R¹ is hydrogen.
 7. A compound according toclaim 1, wherein R² is halo; cyano; aminocarbonyl;alkyloxycarbonylC₁₋₆alkyl; C₁₋₆alkyl substituted with cyano; orC₂₋₆alkenyl substituted with cyano; R^(2a) is halo; cyano;aminocarbonyl; C₁₋₆alkyl substituted with cyano or aminocarbonyl; orC₂₋₆alkenyl substituted with cyano or aminocarbonyl; R³ is halo; cyano;aminocarbonyl; C₁₋₆alkyl substituted with cyano or aminocarbonyl; orC₂₋₆alkenyl substituted with cyano or aminocarbonyl; R⁴ is halo;hydroxy; C₁₋₆alkyl optionally substituted with cyano; C₂₋₆alkenyloptionally substituted with cyano; C₂₋₆alkynyl optionally substitutedwith cyano; C₁₋₆alkyloxy; cyano; nitro; trifluoromethyl; aminocarbonyl;mono- or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkyloxycar bonyl;C₁₋₆alkylcarbonyl; formyl; amino; or mono- or di(C₁₋₄alkyl)amino; and Qis hydrogen, amino, mono- or di-C₁₋₄alkylamino.
 8. A compound accordingto claim 1 wherein n is 0; m is 2; R² is halo, cyano, aminocarbonyl,C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl substituted with cyano;R^(2a) is cyano, aminocarbonyl, C₁₋₆alkyl substituted with cyano, orC₂₋₆alkenyl substituted with cyano; R³ is cyano, C₁₋₄alkyl substitutedwith cyano, or C₂₋₄alkenyl substituted with cyano; R⁴ is halo, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy, cyano, nitro, oramino; and Q is hydrogen.
 9. A compound according to claim 1 wherein R²is cyano, or aminocarbonyl; R^(2a) is cyano, aminocarbonyl, C₁₋₄alkylsubstituted with cyano, or C₂₋₄alkenyl substituted with cyano; R³ isC₁₋₄alkyl substituted with cyano, or C₂₋₄alkenyl substituted with cyano;R⁴ is halo, C₁₋₄alkyl, or C₁₋₄alkyloxy; and Q is hydrogen.
 10. Acompound according to claim 1 wherein -A-B— is a radical of formula—CH₂—CH₂—  (c-3); and R³ is C₁₋₆alkyl substituted with cyano oraminocarbonyl; or C₂₋₆alkenyl substituted with cyano or aminocarbonyl.11. A compound according to claim 10, wherein R³ is C₂₋₆alkylsubstituted with cyano, or C₂₋₆alkenyl substituted with cyano.
 12. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and as active ingredient a therapeutically effective amount of acompound as claimed in claim
 1. 13. A process for preparing apharmaceutical composition as claimed in claim 12, said processcomprising mixing a compound as claimed in claim 1 with the carrier. 14.A process for preparing a compound as claimed in claim 1, said processcomprising: (a) reacting an intermediate of formula (II-a) or (II-b)with an intermediate of formula (III-a) or (III-b), in a suitablesolvent:

wherein each W independently represents a suitable leaving group; (b)reacting the bicyclic derivative (IV) with an intermediate (V), in asuitable solvent:

wherein W represents an appropriate leaving group; (c) preparingcompounds of formula (I-a), which are compounds of formula (I) wherein-A-B— is —CH₂—CH₂— by reacting a pyrimidine derivative (VI) wherein eachW is a leaving group, with an aromatic amine of formula (VII):

(d) converting the compounds of formula (I-a) to the correspondingcompounds (I-b) which are compounds of formula (I) wherein -A-B— is—CH═CH—, by an elimination reaction, in particular by eliminatinghydrogen from a corresponding saturated analog (I-a), using anappropriate dehydrogenating reagent:

(j) converting compounds of formula (I) into each other by appropriatefunction group transformation reactions; and (k) if desired, preparingsalt-forms by treating the free base or acid form of a compound offormula (I) with a suitable acid or base; or vice versa converting thesalt forms into the free base or acid form of a compound of formula (I)by treatment with a suitable base or acid.
 15. A compound according toclaim 1 wherein -A-B— is a radical of formula—CH═CH—  (c-6); and R³ is C₁₋₆alkyl substituted with cyano oraminocarbonyl; or C₂₋₆alkenyl substituted with cyano or aminocarbonyl.16. A compound selected from the group consisting of:

an N-oxide; a pharmaceutically acceptable addition salt; a quaternaryamine; or a stereochemically isomeric form thereof.
 17. A compoundselected from the group consisting of:

and an N-oxide; a pharmaceutically acceptable addition salt; aquaternary amine; or a stereochemically isomeric form thereof.